One of Leon's unlockable bonus weapons is called Matilda.
This is also a shout-out to Resident Evil 2 as the main gun itself is the VP 70 handgun Leon used in that game. You could find the parts to upgrade Leon's handgun to the Matilda, and Hunk had one listed as the Matilda in his inventory in "The 4th Survivor" subplot.
Another reference to the film: the hardest difficulty setting is "Professional".
In Chapter 3-1, after defeating the first Garrador and turning off the flame barrier, three whiteheads in red robes greet Leon when he moves up the stairs. The first whitehead points at Leon and shouts, then runs back the way he came. He ends up standing in a corner facing the wall, like Mike at the end of The Blair Witch Project.
Krauser's use of a bow in Mercenaries may be a shout-out to the Rambo films. Heck, the guy is so 80's action movie personified he should be headlining Contra, not being a second-tier villain in a horror shooter.
It's been noted that the game contains a lot of similarities with Dagon, an adaptation of The Shadow Over Innsmouth. The inhuman villagers armed primarily with melee weapons stalking a lone protagonist, the setting in rural Spain, and the religious cult revolving around betentacled abominations are all similarities. A random villager even looks almost exactly like the Merchant.
In one of the castle rooms, you can find some firespitting statues of dragons. They are almost identical to the weapon Ifrit from the first Devil May Cry game.
The ending is exactly like the one for Devil May Cry, though a jetski is used rather than a biplane which Dante used to escape. In fact, one of the early builds of Resident Evil 4 was turned into Devil May Cry due it straying too far from being Resident Evil.
Help the trapped dog early on and he'll come back to help Leon in the first El Gigante fight. The dog is none other than Hewie from Haunting Ground.
The situation and result are a reference to the ancient Roman fable Androcles and the Lion.
The final part of the game in "Separate Ways", when you need to get Leon the rocket launcher, seems to be based off of part of a map (oil rig) in Counter-Strike.
The Plagas bear more than a passing resemblance to the parasites in Parasyte. Specifically, a normal human walking towards you with a quickly-whipping mass of bladed tentacles and eyestalks sticking out of his neck.
Having to navigate up ladders and stairs while someone rolls barrels down the stairs in the Tower in Chapter 4-4. Some of the barrels are on fire. Early 2D Donkey Kong, anyone?
Speaking of 2D platformers, the Cathedral —if viewed from the exit — would look like an old 2D platformer, with the statue's hands being elevators between platforms.
"It", aka U3, looks like a centaur from the Fallout series of games, particularly the earlier games. Its second form even ends up with two heads, like the Fallout centaur.
The section right after the encounter with It is a couple of large tents set up with barrels around them, with crates and boxes stacked inside. Set in a nook between two cliffs, the way forward is down a ladder into the ground. Like some areas and random encounters in the early Fallout games.
The limited-weight elevator that Leon rides up to the top of the Tower in Chapter 4-4 is a shout-out to the first Metal Gear Solid game. Snake's on an elevator that won't rise because it's at its weight limit due to invisible enemies being on board.
The paintings of the dead in the portrait puzzle room seem like a clear reference to Silent Hill, and its many ominous paintings.
The giant swinging axe-like blades that Leon must pass through after dealing with the Novistadores in the sewer are a shoutout to the very similar series of traps in the first Tomb Raider game.
Ada's swan dive off of the drilling rig at the end of the game is a shoutout to Lara's iconic swan dive move.
Ada also climbs onto a ledge up by doing a forward handstand, like Lara Croft's special handstand method of climbing up onto a ledge.
When Leon's dealing with the ancient underground ruins, there are a couple of sarcophaguses in and underground cavern. He loots a jeweled scepter from one grave, which means he's literally raiding a tomb for treasure. He later does some platforming in above ground ancient ruins in the final confrontation with Krauser. Both are ironic aspects of the Tomb Raider games.
Ashley and Ada get short of breath after running a ways. Harry Mason did the same in 1999 in Resident Evil's main rival Silent Hill 1.
Krauser's super-soldier "charting a new course for the world" is a shout-out to Metal Gear Solid.
One item that consistently puzzles players are the crates containing snakes. How would you get a full grown snake in a box? It crawled into the box as a tiny snake, and grew to full size there. This implies enough creatures coming to the box for the snake to live and grow on.