(Ninjaed.)
There are various other nascent, dormant and sidelined parties sitting in the wings. I'm sure the vacuum would be filled almost immediately, and settled into a new two-party-main-split.
The GOP are relative newcomers to the game (the "Grand Old Party" name proves that at least Leftpondians have some sort of concept of irony, after all!), and Democrat vs. Republican is just the current choice. In less recent times there were Whigs, Federalists, Anti-Masonics, (Anti-)Jacksonians, Know-Nothings and others.
Looking forward, we've got the current anticipating No Label movement (though if they became a "top-two-party, vs. any other 'swing' flavour" then it would probably add to irony), perhaps the Greens might plant themselves as a firm envirocratic stance in the system (doubtful) or the Tea Party/Trumpian/Hyper-Libertarian parts of the shattered (R) base just do a T1000 and reform into a slightly more deranged opposition to the 'left'-wing of US politics. It could easily be the way for moving into Handmaid's Tale territory, with the right charismatic and evangelic figures.
...I can't see a rebalancing moving things too far that way, but the pressures towards (or across) the current political centre (by US terms (if not spelling!)) aren't really there, with not enough high-power moderate-Republicans and not much reason to see a left-of-Democrat pull swaying the relevent overton window, unless they also decide to cleave in twain.
Of course, such predictions are difficult. Especially about the future....