The T-Virus now working on just any dead body nearby, including ones from a graveyard that had been rotting for decades. Despite being a homage to Code: Veronica, where the first zombies you see in the game pull themselves out of graves presumably due to the T-virus soaking into the ground, no such explanation is given in the film proper, and this effect is forgotten in the rest of films just as swiftly as it is brought to this one.
The heroes investigate the helipad and take care of several guards stationed there. When Alice goes inside and starts demanding the helicopter to take off, Major Cain suddenly materializes literally behind her back with Angie held hostage and the rest of the Umbrella forces also gathered there. Such an Offscreen Teleportation is not explained in any way.
The T-Virus being now able to cause a global drought, for completely unexplained reasons. How does that even work in-universe?
Carlos showing signs of infection after being bitten by L.J despite the fact that he had been injected with the anti-virus in the previous film.
The fact that one of the Alice clones knows how to use the laser grid (and does it skillfully and just in time to kill Tyrant-Isaacs and save Alice). The clones were made to reproduce an amnesiac, disoriented Alice from the first film, and that particular clone was choking and shaking upon leaving her jar only minutes earlier. The original script at least justified it by having L.J accompany Alice down to the facility and be the one to activate the laser grid while acting as Mission Control.
The worldwide drought thing from Extinction? Forget that part, nevermind; the water all came back.
Umbrella revealing to have sonehow built a gigantic city-sized base of operations right underneath Tokyo, the world's largest and most heavily populated city, and on top of that, design said base with a helicopter landing bay that uses a busy intersection and pedestrian crossing as the entrance. If the world hadn't ended, how exactly would that even work in a busy urban city?
Zombies mutating into Majinis and learning to burrow deep into the ground for some reason, despite having been portrayed in the previous films as typical Romero-styled shamblers.
Wesker being now able to keep stable his mutation without eating people (or so it looks, given that he seems to be not interested anymore on devouring Alice and the US Army has not revolted against him like his former Arcadia crew) comes to no explanation. The novelization explains that the Wesker killed in Afterlife was a clone, but there is no traces of this in the film proper.
The Red Queen turning out to be active and somehow free from the Hive. Not to talk about her being now bent on destroying humanity through the T-Virus instead of saving them from it as she was programmed to do in the first film.
The Lickers now having the custom to drag alive prey and coccoon them without causing any harm. No Licker from the previous films had shown such behavior, or any behavior besides immediately killing any living being on sight, and it only feels as a cheap excuse to create drama through Becky's scary abduction and miraculous rescue (and probably to force in a Homage to Aliens).
Alice, who is still human and without powers from the previous installment, surviving to Rain's death palm strike despite the comparatively bigger Luther having died of the exact same blow seconds earlier (X-ray comparison included onscreen).
The revelation by the Red Queen that all the events in Retribution were all somehow a plan concocted by Wesker to wipe out Umbrella's main enemies together doesn't make sense in any conceivable way. For starters, all of those deceived enemies were either regular human fighters whom Wesker would have had no trouble murdering by himself or American military that would be overrun by the T-virus invasion in a matter of time. Not less importantly, by the prologue of Retribution Umbrella had finally achieved their years-long goal to capture Alice, so they had literally no reason to stage any kind of rescue for her (and destroy Umbrella Prime in the process) only to attract her insignificant allies. Even the additional goal given in the novelization, namely that Wesker wanted them to eliminate his rival Dania Cardoza for him, falls flat in that very book when not only is Dania revealed to be a clone, but Wesker outwits and kills her real self later without any difficulty.
Even if we count on the novelization to explain why the Red Queen is now good after having turned evil the previous film (in this case, because she did not really turn evil in the first place), the fact that she claims to have fundamental laws against killing Umbrella workers, explicitly requiring Alicia to fire Wesker so the Red Queen can act against him, seems to overlook that she butchered an entire facility of Umbrella workers in the first film. It is even phrased in a way that implies she had always been this way instead of it being a recent reprogramming, which would have justified it. It is possible that what she meant was that she has programmed laws that prevent her from killing members of Umbrella's high command (the rank-and-file workers from the first movie were fair game, whereas Wesker was a high level employee, so the Red Queen could not kill him without him being fired), but a simple single wording change in the script would have made it less confusing and more justified.
Dr. Isaacs being suddenly revealed to be the co-owner of Umbrella, Wesker's direct superior and the mastermind behind the entire saga (very probably due to Iain Glen becoming much more famous thanks to Game of Thrones since the third film), even though Extinction had established he was just a high ranked Umbrella scientist who was still subordinate to people like Wesker and Slater. It doesn't help that he's treated like Alice's archenemy despite the fact that his first clone was just an one off villain and that the original Isaacs (and his second clone from this film) had no prior relationship to (this) Alice. As a finishing blow, it is also revealed here that Wesker himself is actually a mere employee, not even a shareholder, despite all his appearances in the saga had explicitly informed he was the corporation's chairman and shown him as the head of the board of directors. While the implied explanation is that Wesker was merely acting chairman in Isaac's name until the virus had wiped everyone except Umbrella out, this had never been remotely lampshaded or hinted in the previous films, but rather the very opposite.
Umbrella now having an antidote for the T-Virus that destroys all mutated creatures. A plot point of the entire franchise had been that there was no viable way to dispose of the T-monsters or to contain an outbreak except by traditional means, and those were precisely all the measures Umbrella had been forced to take (injecting antidotes before the mutation, manually executing the infectee afterwards if not possible, killing entire facilities to prevent contagion, nuking up cities to be sure, trying to domesticate or control the creatures, etc). Even the charitable interpretation that they just devised the antidote during the events of this film fails to fit the next revelation that Umbrella concocted the global apocalypse, because it would mean the corporation peformed the spectacular stunt of starting an uncontrollable outbreak without knowing whether they would develop someday an efficient way to stop it.
The Isaacs clone somehow finding out that Alice knows about said antidote, thus kicking all the plot of the film when he informs Wesker, despite she had never said a word about it in her interrogation. Even if it all amounts to both the clone and Wesker assuming the worst about the presence of Alice on the zone, it is still an oddity.
The T-Virus outbreak being actually engineered by Umbrella all along in order to purge humanity and build a new global society with a caste of rich and powerful in cryostasis. The first film had shown that the original outbreak was an event that had happened completely outside the corporation's control, as it was released by Spence during his attempt to steal the virus. In the first two films Umbrella's main motivation was genuinely trying to avoid a global disaster, to the point of nuking up Raccoon City in a risky coverup maneuver in order to stop the virus, and the third one showed that the Umbrella board was desperate and clearly not in control of the post-outbreak situation (even Dr. Isaacs's idea to rebuild the world with zombie workers was just a novelty born from those circumstances). The new twist that everything was planned had never been foreshadowed and doesn't make sense given Umbrella's attitude up to that point. It also contains an additional absurdity because those executives in cryostasis happen to be stored under the Hive, just under the place they decided to nuke up in Apocalypse after it suffered a containment break. Good thing it was nuke-proof, becase they took a massive risk given their supposed plan.
In the opening scroll Alice mentions that the government was the one that nuked Raccoon City, as if to bring up a weak explanation to the above. Again, this goes against film continuity, because it was Umbrella itself which opted to destroy the city in order to both prevent the outbreak spreading out of control and cover it up (not that it makes sense for for a private corporation to have the means to issue a stealth bomber and launch a nuclear strike against a US city with no involvement from the government, but this is that kind of film), and Alice should perfectly know this.
A bigger revelation yet: Alice being the clone of Alicia Marcus, as well as an Unwitting Pawn of the latter's will to thwart Isaacs's plans. Previous films had established pretty solidly that Alice was her own person, specifically just a rebellious security operative who had managed to bond with the T-Virus, and that there was no more mystery at it. Even her longing conflict with Umbrella had always been exclusively caused by them, as they would try to capitalize on her bond to turn her into a living weapon (like Cain did in Apocalypse), perform experiments with her DNA despite they should already have it (Dr. Isaacs in Extinction), devour said DNA to contain a personal mutation (Wesker in Afterlife), find out why did she betray the corporation (the Red Queen in Retribution), or merely endanger people she wanted to protect (all the films). The revelation that Alice was a clone of someone, that she was part of a plan against Umbrella by said someone all along, and that said someone was who the T-Virus was specifically made for since the beginning (forcefully retconning the virus's origin by Dr. Ashford in Apocalypse) came completely from nowhere.
Related to the previous, Alice's line about how she "woke up in the mansion when everything started and has no memory from before" seems to imply Final Chapter is officially pulling Broad Strokes on the first movie, because she did recover memories from her earlier life with Spence in that film - which were precisely why she betrayed the corporation to begin with! While by this point of the saga Alice has already tasted a fair bit of Clone Angst and Fake Memories, she had never previously shown to have suspicions that said memories were fake, nor the audience had had reasons to suspect they might be.
Wesker dying due to the Red Queen crushing his leg with a door is absurd next to previous films depicting him surviving helicopter crashes, pseudo-nuclear explosions and endless point blank gunshots to the chest and head thanks to his T-Virus powers. A leg wound like that would hardly kill a regular human without Wesker's Healing Factor. Not even the novelization's author, who tried his hardest to justify it on the novel, really bought it for a second, as it is later shown Wesker survived.
Alice deducing that Doc is Umbrella's informant, and somehow deliberately inserting an empty clip in the latter's gun, all in spite Doc had never displayed any suspicious traits onscreen up to this point. The explanation of him being still alive makes no sense either, since zombies lack the capability to distinct Umbrella workers from other uninfected humans, and he could have very well died by one of Umbrella's own traps or even before the group reached the Hive, making the whole cover pretty pointless. Alice is pretty damn lucky Doc never got to try that gun out in case they met more than one monster in the facility halls, else he would quickly blow Alice's trick.
