Sans - Undertale
memeworthy? yes. a legitimately hard boss fight that feels rewarding to finally beat? also yes.
Nightmare King Grimm - Hollow Knight
i could easily list off a dozen different bosses from Hollow Knight, but if I had to choose just one, it would be this one just due to how hard it is.
Ultra Necrozma - Pokemon Ultra Sun & Ultra Moon
or as I like to refer to it, Nuzlocke-Killer Necrozma. its hard to find anyone who did not immediately get their whole team OHKO's on their first try at this boss
Agent 2 / Commander Tartar - Splatoon 2: Octo Expansion
the Octo Expansion is the best thing to come out of Splatoon so far, and my god the final boss hits you like a truck. this one goes down as one of my most memorable boss fights ever.