Serious question because I've never actually had to consider these things lol. But how much of a difference is there between a 2 seed and 3 seed? Asking since those are the seeds lined up to meet in the Sweet 16. I guess the 3 has a slightly harder road to Sweet 16?

Odds are 20% lower of an upset from the #3 seed to #5 seed. And, 11 over 6 seed is one of the most common upsets to happen, so that can also be in play (usually that 11 seed is a play-in high major team, but still).
But playing the six seed instead of the five seed could be the difference of playing a St. Mary's or Gonzaga instead of a Maryland or Arizona.