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I think I've finally figured it out! Regarding the ultimate antagonist of a series, if there's multiple BigBads then this only applies to the final or ultimate one (like The First)
Spoilers for all four Joss Whedon series follow
With the exception of the villain in Dollhouse, who had unique circumstances around him, the ultimate antagonist of Joss Whedon series is never killed off.
Regarding the BigBads:
- In Buffy, you have The First, final antagonist and most dangerous
- In Angel, you have the Senior Partners, who run Wolfram & Hart
- In Firefly you have the Parliament, who run the Alliance
- In Avengers you have Thanos, the guy behind Loki and Ronan who is confirmed as the villain of Avengers: Infinity War
- The First cannot be killed, but at least his army is destroyed rendering him powerless
- The Circle of the Black Thorn is destroyed, and the Senior Partners send a huge army after Angel. We don't know the outcome of the battle though I'd like to think that Angel, Spike, Connor, and Illyria all survive (we know Gunn's doomed) and take out the army thus rendering the Senior Partners powerless.
- In Firefly, or rather Serenity, Mal plays a recording to show that the Alliance created the Reavers and covered it up, weakening their regime, but the Parliament will want revenge on Mal, although no longer hunting Simon and River.
- Is there any reason to doubt something similar will happen with Thanos? I heard a rumor that Nebula defeats him and he goes Emo and lives on a farm, which is kinda on the scale of The First, since we actually see both beyond a small nonspeaking cameo.
And of course, it isn't just final antagonists that have a pattern. He usually kills off two main characters at the end, the second of which is a really cool or fan favorite character, and neither of which is THE main character. And sometimes kills main characters in the middle: Spoilers follow
And there's nothing beyond them
- In Buffy, Anya and Spike are killed in the final episode. Also there's Tara near the end of Season 6
- In Firefly, Book and Wash are killed in Serenity.
- In Dollhouse, Paul and Topher are killed in the final episode, also Mr. Dominic and Ivy presumably get it before the futuristic episodes and November and Boyd are killed near the end of the present day arc
- In Angel, Lindsey McDonald and Wesley are killed off in the final episode. There's also Gunn but he still lives by the end of the final episode, his death will occur after. And of course they killed off Doyle, Cordelia, and Fred in the middle.
- Avengers: Infinity War is five years from now but we've got our "middle" death: Coulson, although like Spike he comes back. For the first character to be killed in Infinity War Part II, it'll probably be one of the Avengers' allies (Rhodey, Bucky, Sif, etc.), Nick Fury, or one of the Guardians of the Galaxy (besides Quill), and according to polls, Loki is the fan-favorite character so Joss Whedon has to kill him second. Unless of course someone else is directing Infinity War.
EDIT: Actually, Joss Whedon isn't directing Infinity War so his rules don't apply, although he did set in stone that Thanos kills all the Avengers as seen in Tony Stark's vision