The Cardinals built a 24-8 lead in the game's first 11 minutes and fought off a Tennessee charge to set up a meeting Saturday with top-seeded North Carolina in the title game of the East Region.
Smith hit two three-pointers during the early run and combined with McGee to score 15 of Louisville's 24 points in the game-opening outburst.
Tennessee fought back to within seven at the half and closed to within two with 15:24 remaining in the game. But Louisville then ran off eight straight points to regain command and coasted from there.
After missing their first three shots in the second half, the Cardinals made seven in a row.
The Volunteers, who briefly held down the No. 1 spot in the national rankings this season, had been trying to reach the tournament's regional finals for the first time in school history.