Louisville stormed in front by 16 inside the 9-minute mark and Oregon came no closer than six the rest of the way.
The Cardinals, the No. 1 seeded team in the entire NCAA Tournament, will go after the Midwest Region title on Sunday when they meet second-seeded Duke. The Blue Devils prevailed over Michigan State in Friday's second regional semifinal 71-61.
Louisville is seeking its second trip to the Final Four in as many years and its third appearance since winning the national championship 27 seasons ago.
The Cardinals lost to eventual champion Kentucky in last year's national semifinals.
Smith went 9-of-16 from the field and 12-of-14 from the foul line in leading a team that hit 53 percent of its shots.
Oregon held its own on the backboards, had one less turnover than did Louisville and made one more 3-pointer. The Ducks, however, connected on only 44 percent from the field and could not finish off a second-half comeback bid.
Kevin Ware added 11 points for Louisville (32-5), which will take a 13-game winning streak into the regional final. The Cardinals will be one of three teams from the Big East playing for the right to go to the Final Four, although two of those clubs -- Marquette and Syracuse -- will be facing each other Saturday in the finals of the East Region.
Oregon (28-9) was led by 15 points from E.J. Singler. The Ducks were the last of the five tournament teams from the Pacific-12 Conference still alive and that league finished the event with a 5-5 record.