"I can't say enough about our guys who pitched really, really well, played very good defense," Florida Atlantic coach John McCormack said. "Now we've just got to do it all again tomorrow."
Santiago's homer was the first hit for the second-seeded Owls (42-21) and one of three all night. But the Tar Heels (54-9), while managing 12 hits, left 15 runners on base and repeatedly came up empty in key moments.
Now the Tar Heels, who started 39-2 and won the Atlantic Coast Conference title, must pick themselves up from a regional loss that looked similar to last year's loss to St. John's on a walkoff homer.
UNC hasn't lost consecutive games all season.
"This club has pretty much led themselves all year," UNC coach Mike Fox said. "I trust my team. We've got some good leaders in there. I'm sure they're not very happy. We do have another game to play, so it'll be up to them and us and everybody to shake this one off and come into the ballpark tomorrow and be ready to play."
Before Santiago's hit, North Carolina appeared to be in control with Hobbs Johnson pitching six no-hit innings. UNC led 2-0 behind an RBI single by Colin Moran in the first and a sacrifice fly by Michael Russell in the fifth.
But Johnson said he struggled with his control and eventually left after allowing his fifth walk in the seventh. Three batters later, Santiago knocked a pitch from reliever Trevor Kelley (2-1) over the left-field wall for the 3-2 lead.
"Everyone was frustrated just because I felt like we were hitting balls hard most of the night and they were getting caught," Santiago said. "But we have some good leadership that kept everyone up. Our pitchers kept us in the game, which is big-time. Our defense kept us in the game. Then I was able to get the big hit."
Reliever Michael Sylvestri (4-2) earned the win by allowing no hits in two scoreless innings.