Peyton Siva contributed 10 of his 16 points down the stretch as the top-ranked Cardinals (33-5) overcame a gruesome injury to guard Kevin Ware and advanced to the Final Four for the second straight year.
Gorgui Dieng added 14 points and 11 rebounds and Luke Hancock came off the bench for 10 points for Louisville, which reached its 10th all-time national semifinals berth and logged a 14th straight win overall.
Louisville now goes on to face Wichita State in Atlanta April 6.
Mason Plumlee provided 17 points and 12 rebounds for the Blue Devils (30-6), which lost a regional final for the first time since 1998.
Quinn Cook and Seth Curry each scored 12 points for Duke.
Ware was hospitalized after gruesomely breaking a leg in the first half. Louisville was leading 21-20 when he hurtled toward the sideline while contesting a 3-point try. The sophomore landed awkwardly and suffered what school officials confirmed was a broken leg, causing visible distress among his teammates.
Ware was resting comfortably after being hospitalized, CBS Sports reported.