Brook Lopez led 11th-seeded Stanford (18-13) with 18 points, but the Cardinal did little to validate their surprise at-large selection.
Stanford had to travel more than 2,400 miles across the country and was playing at 9:30 a.m. PDT. The Cardinal never found its footing against Louisville's aggressive full-court pressure that harassed the Cardinal all game long.
Stanford turned the ball over 21 times and struggled with foul trouble. Twin brothers Robin and Brook Lopez both picked up two quick fouls, freeing up the middle for the Cardinals, who outscored Stanford in the paint 36-22 despite being at a significant size disadvantage.
The Cardinals pressed and trapped their way to the lead, overwhelming Stanford. Thousands of Louisville fans who turned Rupp Arena into a sea of red roared their approval.
Pitino had worried about his freshmen-laden team's ability to adjust to the pressure of the NCAA tournament, but the Cardinals hardly seemed intimidated by the stage.
The quartet of Smith, Sosa, Caracter and Clark combined for 50 points and played with the kind of steadiness that propelled Louisville's surprising rise to second-place in the Big East.
Louisville opened the game on a 12-2 run, using full-court pressure to frustrate Stanford into careless turnovers on one end of the floor, then smartly getting open shots at the other end.
With Robin Lopez languishing on the bench after collecting his second foul just three minutes in, the Cardinals feasted on a suddenly wide-open lane. Louisville put together a 22-4 run midway through the first half that broke it open by getting to the foul line, knocking down 3-pointers and continually forcing the Cardinal into bad decisions.
During one sequence, Smith sank a 3-pointer from the corner. Stanford threw a long inbounds pass over Louisville's press, only to have the ball fall into the hands of Clark, who finished with a dunk, drawing an intentional foul in the process.
Clark made one of two free throws, and Caracter added a pair on the ensuing possession. Sosa and Smith then hit back-to-back 3-pointers as Louisville's lead eventually ballooned to 46-20 at the half.