It could happen, but it's unlikely.
Right now, the only chance I see of this happening is a popular Democratic president winning reelection, and it probably has to be a Democrat who takes over after a Republican President. So, the earliest it could happen is 2024.
The 2012 Senate election in Missori is instructive, pitting an incumbent Democrat against an incompetent challenger. Exit polls showed a higher white vote for Akin.
http://elections.nytimes.com/2012/results/senate/exit-polls?state=moHe technically didn't get a majority as a high number of voters (over 6 percent) supported the libertarian candidate. And that's another reason it might not happen in the current environment. If a Democrat looks like he or she will win in a landslide, voters who don't like the Republican might support a third-party choice.