- At one point in Chris and Piers' story, you come across a playground. You can actually play on the playground equipment. Ada, of all people, can take a moment from her duties to take a ride down a playground slide too.
- Chris and Piers' become ten times funnier when you notice that they look absolutely freaking serious when playing on the playground equipment.
- If facing two J'avo as Ada at the playground, one of them will... jump on the other's shoulder.
- When Sherry and Jake reunite in a locker room after being captured by Neo Umbrella, Jake immediately looks away from Sherry in embarrassment because she's wearing a fairly revealing patient's outfit. Sherry looks down at herself and quickly ducks behind a locker door. A little bit later, when Sherry is changing in front of Jake (they're pressed for time and not exactly spoiled for choice of changing rooms) and facing away. Jake takes a long look at her back, then turns away to find some clothes, all without changing his expression or acting as if anything actually happened.
- Jake and Sherry jump into a metal bin to hide from Ustanak. Whispered bickering ensues about who’s touching whom.
Sherry: “Keep your hands to yourself!”Jake: “Hey, you’re the one rubbing up on me. Besides, what makes you think you’re my type?”Sherry: “I would shoot you if I didn’t need you alive.”
- Yet another one from the Jake campaign: "You jarheads all look the same to me, sorry." This, coming from an Action Genre Hero Guy, when said to Chris and Piers, who both have full heads of curly hair.
- In Leon's story, the Rasklapanje's hand can be shot off and attacked. If the attack button is pressed near a microwave, instead of throwing the hand away, Leon will shove it in the microwave, and we get to hear the sound of the hand blowing up. In Chris and Piers' campaign, you can shove it down a toilet. In Ada's campaign on the Carrier, you can throw it into a pot of boiling water in the kitchen.
- The cutscene before the Ustanak fight at the plane crash site:
Jake: "Him again?"Leon: "Friend of yours?"Jake: "More like an ex-girlfriend. Guy doesn't know when to quit."Leon: "Welcome to the club."*Beat*Leon: "You get used to it."
- The final fight sequence in Jake and Sherry's campaign is possibly this game's equivalent of Chris punching a boulder, which means it's pretty damn hilarious. Still doubles as a Crowning Moment of Awesome, though.
Jake: Christ almighty, what does it take to lose this guy?!Ustanak: *Roars defiantly*Jake: Jesus, TAKE THE HINT!
- Even better is Jake's unrestrained opinions on the matter, wherein he's saying what we were all thinking back when Nemesis was hunting us in Raccoon City.
- In one chapter in the Sherry/Jake storyline, there's a section where one plays a piano to get a medallion. Jake plays Chopin's "Revolutionary Etude", Sherry plays "Twinkle Twinkle, Little Star"/"Alphabet Song".
- Leon just before he and Helena fight the infected Simmons for the second time. Possibly funnier if you are a fan of Quantum Leap.
(The duo watch as Simmons turns into a giant monster)Helena: He's...Huge!Leon: ...Oh boy.
- Give a look to the Whoppers action figures in the Collections and laugh at their poses.
- The way the Ustanak casually kicks Jake's gun into the lava pit is so unusually dickish for a Tyrant that it's hilarious.
- A meta joke one with Ada, who always cryptically helps Leon, and Leon during his story. She hands him a ring.
Leon: A ring?Ada: Don't get the wrong idea. It'll make sense later.(Going with the flow) Leon: Okay.
- Let's face it, Sherry and Jake have the most hilarious dynamic as a duo in the entire game.
Sherry: (after Jake falls down a two-storey building) Jake! Are you OK?!Jake: (recovering) I've had worse spills, though it's too bad I don't have your healing factor.
- Ada's partner character, Agent, doesn't exist in the story. He was patched into the game later so that players could play Ada's campaign in co-op. Because of this, Agent doesn't participate in cutscenes or puzzles, he can't open doors or chests and Ada sometimes gets into situations that would be easily solved if the Agent would just help her, leading to comical moments. Best shown off here