There simply aren't enough Hillary Clinton voters who will cross party lines and vote for Republicans to make up for a 10-point Trump loss.
The battle for control of the Senate is already a nailbiter, and if Trump loses by big enough margins, Ryan's historically large majority in the House of Representatives could go down with Trump too.
So Ryan is going all in to try to save himself and his party's congressional majority.
We haven't seen something quite like this happen in presidential politics since 1996, when congressional Republicans ditched nominee Bob Dole in the final weeks before the election.
But there's a big difference between then and now: Dole and his supporters accepted the shift quietly. It's almost guaranteed Trump and his supporters won't. And that could be a big problem for congressional Republicans who need the party's base of core supporters to win in tight races.
We're already seeing that dynamic play out. On Sunday, four vulnerable Senate Republican candidates reversed their support for him and said they couldn't vote for him. But one, Joe Heck of Nevada, got booed when he said it.
Trump's performance yesterday didn't make life easier for Republicans who want to avoid a backlash: Trump did well enough to satisfy his base, but not well enough to win over any new voters.
Speaking of which, there's no guarantee that ditching Trump now will help win over sceptical voters.
But just because Ryan's out - though, as many Democrats were quick to point out, he hasn't recinded his endorsement - doesn't mean the rest of the Republican Party is.
Republican National Committee Chairman Reince Priebus was photographed flying with Trump to the debate in St Louis, a signal the GOP hasn't completely cut off its nominee.
And Indiana Governor Mike Pence made it clear he's staying on as Trump's vice-presidential nominee, despite their relationship being on the rocks.
The question now for Republicans nervous about sharing the ballot with Trump: Do they follow Ryan's lead, and try to save themselves, at the risk of upsetting voters in their own party? Or do they stick with Trump to the bitter end, whatever that may be?