Remember, spoilers are unmarked for this trope. You have been warned.
Season One
"Return to Spider Skull Island" is the season finale and ends with Hank and Dean dying. As the series hadn't yet been renewed when this episode was written, it could serve as the series finale if needed. Thankfully, it was renewed and the season two premiere had some fun with this, replacing Hank and Dean in the opening credits it with Rusty and Jonas Jr. as a new set of "Venture Brothers" (before going into the plot point that Hank and Dean have died before, but Rusty brings them back as clones).
Season Three
"The Family that Slays Together Stays Together Part II" is the season finale, the second half of a two-parter, and really the end of an "episode trilogy" as the story goes back to "ORB". After being pursued by the O.S.I. trying to kill him, Brock orchestrates a Let's You and Him Fight battle between the Monarch and the O.S.I. It's interrupted when Sgt. Hatred leads an army of spare Hank and Dean clones into the fray, ending with all of clones destroyed, Henchman #24 dying, and Brock quitting. The Stinger reveals Brock was set up by Molotov and Hunter, who has since joined her "Blackhearts" all-women assassin squad, using Brock to eliminate their competition.
"Operation PROM" is the season finale and leads to one of the biggest shakeups of the Venture-verse so far. General Treister retires and, after a Secret Test of Character, leaves Col. Gathers in charge of the O.S.I. Henchman 21, fed up with being a Noble Top Enforcer to the Monarch, quits to join SPHINX. Molotov is revealed to have been the rookie SPHINX agent in the background of previous episodes, steals Monstroso claiming that he is her lover, and chooses to go off a cliff rather than surrender to Brock.
Season Six
The pre-season one-hour special "All This and Gargantua-2" dramatically shakes up the Venture-verse for nearly every significant character in one way or another. Anyone Can Die as Jonas Jr., General Treister, the Investors, the Sovereign, eight of the Council of 13, Zero, and (not witnessed on-screen but implied) the Murderous Moppets/Pupa Twins all find out. Jonas Jr. leaves his multi-billion dollar technology company to Rusty, moving the series main setting to New York City. Phantom Limb is back in the Guild, and on the Council of 13 at that. Prof. Impossible reconciles with Sally and leaves villainy behind. Dr. Killinger is in the same class of Ambiguously Human superbeings as the Investors and quite possibly their fourth brother.
Season Seven
The season-opening "Morphic Trilogy" consists of three "Whams" in a row:
"The Venture Bros and the Curse of the Haunted Problem" reveals that the "Problem Light" from season one's "Careers in Science" has been keeping Jonas Sr.'s disembodied head alive since the "Movie Night Massacre" of the 1980s, its blinking was to signify that he had regained consciousness, and he manages to tap into VenTech Tower's systems.
"The Rorqual Affair" reveals that Wide Wale has for a while known that the Monarch was moonlighting as the Blue Morpho, and that he still has it out for him because his real name is Chester Ong, and the Monarch was responsible for the death of his brother Douglas Ong, a.k.a. Dr. Dugong, from season three's "Tears of a Sea Cow". With Red Death's help, Dr. Mrs. The Monarch and 21 infiltrate an OSI Dummy Corp. building to find information revealing that Dr. Dugong is still alive to bring him to Wide Wale, saving the Monarch's life. In the aftermath, they discover VenTech Tower starting to move, followed by the Morphomobile landing right in front of the door.
Vendata survived Brock's attack in season five's "Bot Seeks Bot" after which he began to recover more of his memories as the original Blue Morpho, and begins to recover more of them when he gets to VenTech Tower and interfaces with the Problem Light, leading to a showdown with Jonas Sr who wants to upload his brain into Blue Morpho's body until a new body can be cloned for him.
The "great man" Kano took a vow of silence for killing was indeed Blue Morpho, after his programming as Venturion led to him nearly killing Rusty in a glitch that led to him remembering his son Malcolm (the Monarch) crying due to Rusty taking his toy. Dr. Z then recovered Venturion from the Venture compound's dumpster and reprogrammed him into Vendata.
Blue Morpho was being blackmailed by Jonas Sr. into doing his dirty work, using the tape he recorded of the two of them having affairs with Jill St. John and Stella Stevens. It's also heavily hinted that Blue Morpho was infertile, and that Jonas Sr. had an affair with his wife, resulting in the conception of Malcolm), making Rusty and the Monarch half-brothers.
Red Death was on Gargantua-1 during the Movie Night Massacre, which was another callback to "Careers in Science", which was a plan formulated by Vendata to arch Jonas. Vendata attempted to confront Jonas with the same blackmail tape that had been used on him years earlier. Jonas taunted him over its contents, and left the airlock control room, with Vendata questioning what to do, but the recovered memory ends before anyone knows who actually opened the airlock, killing nearly all those onboard Gargantua-1, with the only survivors apparently being Red Death (who kept his space helmet on to hide his red skull face), Vendata (as an android), and the future Colonel Bud Manstrong (who was in a different part of the station).
The aftermath of the unapproved "arching" led the Sovereign to disguise himself as SPHINX Commander and taunt the O.S.I. that SPHINX responsible, kicking off the Pyramid Wars between the O.S.I. and SPHINX, for which Brock was drafted into O.S.I. in the first place, making his whole life a lie.
Brock, acting on behalf of O.S.I., makes a deal with the present members of the Guild's Council to jointly arrest Vendata/Blue Morpho for the death of Dr. Jonas Venture Sr., and the deaths of the various Guild members the Monarch and 21 were indirectly responsible for killing in season six, getting them off the hook.
The Action Man finally has the stroke that Dr. Orpheus predicted would result in his death in season one's "Past Tense", which means it has been two years and 17 days since that episode in-universe. (That episode was first broadcast in 2004 and this one was broadcast in 2018.)
The Monarch interrupts the situation, getting Blue Morpho's attention, who recognizes the Monarch as his son just before Jonas uses the PRO.B.L.E.M. to attack him, bringing both of them, as well as the Monarch and Rusty out of the building. They crash land, resulting in the final deaths of Jonas Venture and the Blue Morpho/Venturion/Vendata.
The Stinger reveals that the O.S.I. wants Jonas' head for research purposes.
While "The Inamorata Consequence" is a much calmer episode than the trio of whams above, it still has two particular standout moments. After Dean leaves H.E.L.P.eR Model 2, the latter calls him "Rusty", strongly implying that Dr. Venture himself died and was cloned by Jonas Sr., to add a layer to their Clone Angst. In The Stinger, Dr. Mrs. The Monarch realizes that S-464 is a mole for the Peril Partnership, setting up their influence over the second half of the season.
In "The Forecast Manufacturer", Hank, going crazy over the fact that Sirena hasn't been responding to his messages while the city is in the midst of a blizzard, leaves to the find them. After he gets knocked out and Scare Bear rescues him, he is taken to Dean's dorm where Dean and Sirena are in bed together. Though Hank is still too disoriented from his concussion to realize the gravity of the situation, the audience gets a sizable "Wham" suggesting that the brothers' first big fight is about to happen.
The Guild puts the Monarch and 21 through an ordeal as part of the Monarch's ascension to "level ten" villain status. During the "play", 21 is given a "level four" supervillain status and the Monarch is given a bound/gagged Dr. Venture to kill to complete his initiation. Both the Monarch and 21, upset over the Guild's chicanery, threaten to quit, only for it all to be revealed as a Secret Test of Character. However, at the end, Watch and Ward discover and blab that Dr. Venture and the Monarch are blood-related.
Hank goes through an Adventures in Comaland sequence with the Action Man, during which the latter spills that Hank's mom is apparently a former actress named Bobbi St. Simone. Meanwhile, Dean visits Hank's comatose body in the hospital, revealing that he found out that Dermott is also their brother, and laments that they had grown so apart and he had become jealous of Hank's free-spirited nature. The next morning, Hank disappears from the hospital and goes on the run to find himself, as his "The Bat" persona.
As the series Finale Movie, a couple of bombshells are dropped resolving some of the series' long-running mysteries:
Rusty and The Monarch are not half-brothers as previously implied. They're actually BOTH clones of the original Thaddeus Venture (Monarch slightly altered), with Jonas Sr. providing "Malcolm" to the Fitzcarraldos when they couldn't conceive.
Hank and Dean's mother is not Bobbie St. Simone as Hank was originally told. Instead, it's strongly implied (and outright stated by Doc Hammer in the commentary) that Bobbi's daughter, Debbie, aka the film's Big Bad Mantilla, traded her egg cells to Rusty in exchange for Rusty's help in gaining her mother's invisibility powers. Debbie is thus their biological mother, while, as shown in The Stinger, Rusty carried them in a Uterine Replicator.
In addition, Debbie also happens to be the daughter of Force Majuere, the Guild of Calamtious Intent's former leader and an Arch-Enemy of Jonas Sr., who was usurped and killed by the Sovereign. This makes the boys the biological grandsons of each of the Venture-verses' greatest "hero" (at least publicly) and greatest villain.
