Michael Carter-Williams carried Syracuse back to the Elite Eight with 24 points, five rebounds and four steals as the Orange ousted top-seeded Indiana, 61-50, in the second East Regional semifinal.
Syracuse's zone defense caused problems for the Hoosiers all night, forcing 19 turnovers while holding them to 33 percent shooting, including a dreadful 3-of-15 effort from behind the arc.
Brandon Triche and C.J. Fair chipped in 14 and 11 points, respectively, for the fourth-seeded Orange (29-9), who advanced to the regional final for the second straight year.
They will face a Big East opponent in Marquette on Saturday, as the third- seeded Golden Eagles upended second-seeded Miami-Florida in Thursday's first game at Verizon Center.
The nightcap was headlined by Syracuse's stingy defense, as James Southerland recorded three of the Orange's 10 blocks and helped limit Cody Zeller to 10 points on 3-of-11 shooting.
"We forced him where he wasn't underneath the basket, and we could get help back to him," Syracuse head coach Jim Boeheim said in regards to defending Zeller. "We got back inside quickly on their big guys when they tried to finish around the basket."
Victor Oladipo, a Naismith Award finalist, led the Hoosiers (29-7) with 16 points while Christian Watford added 13 in the loss.
Indiana was held to its lowest point total of the season and joined Gonzaga as the only No. 1 seeds to fall thus far.
The only other time these storied programs met in the NCAA Tournament came in the 1987 title game when Keith Smart's late jumper sealed Indiana's fifth and most recent national championship. There were no late-game heroics this time around because Syracuse dictated play from the opening tip.
A sloppy first half saw the Big Ten regular season champs commit 12 turnovers, just one less than their season average.
Carter-Williams had his way on the other end with 12 first-half points and hit a 3-pointer during a late 7-0 run that gave the Orange their biggest lead, 29-11, with less than four minutes to go.
Indiana scored 11 of the final 16 points of the half to pull within 34-22 at intermission, then scored the first five points of the second half to cut its deficit to single digits.
The margin was six, 38-32, after Oladipo drilled a straightaway 3-pointer with just over 14 minutes remaining, but that was as close as Indiana got.
"We did not do a good enough job on a couple of their guys, especially Michael Carter-Williams and we couldn't get over the hump," Indiana head coach Tom Crean said.
Syracuse, not wanting to duplicate the 13-point halftime lead it blew against Louisville in the Big East tourney title game, went on a 14-5 run to pull away.
Carter-Williams netted 10 during the surge, including a 3-pointer and a free throw for a 52-37 cushion with 7 1/2 minutes to play.
It was a double-digit affair the rest of the way.