He won't be back on Saturday when the seventh-ranked Blue Devils look to fill the void against Utah in the Ameritas Insurance Classic at Madison Square Garden.
Duke (9-1) will go for its eighth consecutive victory, but the road figures to get tougher without the Blue Devils' leading rebounder.
Jefferson's hustle off the bench played a big part in Duke's championship run last season, which included a 63-57 win over Utah in the Sweet 16. Duke's top returning scorer averaged 11.4 points and 10.3 rebounds in his first nine games, but he broke his right foot while diving for a loose ball in practice last week. Jefferson is out indefinitely, though the injury will not require surgery.
''We'll have to keep the ship afloat while he's gone,'' coach Mike Krzyzewski said.
Duke passed Tuesday's first test - albeit a small one - by blowing out Georgia Southern 99-65. Rebounding wasn't an issue for the Blue Devils as they grabbed 55 to the Eagles' 29.
Brandon Ingram and Marshall Plumlee combined for 35 points and 25 rebounds, but Duke's guards accounted for 60 of the other 64. Jefferson's spot in the starting lineup was filled by freshman guard Luke Kennard, while fellow freshman Ingram moved from small forward to power forward.
Chase Jeter will likely see the biggest boost in minutes inside, but he finished with just two points and three rebounds in 17 minutes - the most he's played in his first season - against the Eagles.
''It's a huge period of adjustment for us,'' Krzyzewski said. ''You don't lose Amile and then, `OK, everything's good.' ... Amile was our best big guy.''
Duke played for the first time in 10 days due to final exams, and the Blue Devils won't play another after Utah until they host Elon on Dec. 28. Jefferson's cast is set to come off on Dec. 26.
Duke won the 2K Classic at MSG in November and holds a four-game winning streak there.
Last Saturday's 67-50 loss at Wichita State cost Utah (8-2) its No. 25 ranking. The Runnin' Utes finished with a season-low five assists and a season-high 19 turnovers in their first road game.
A change, symbolized by fresh haircuts, showed up in Wednesday's 99-53 rout of Savannah State. Utah dished out a season-high 30 assists on 37 field goals while turning the ball over 11 times.
''It was time for changes,'' said Kyle Kuzma, who finished with 18 points and five assists. ''We just got back to basics. Everybody shared the ball and that was the biggest reason we had success.''
That unselfishness turned into 60.7 percent shooting and a season-high 11 3-pointers on 21 attempts, a far cry from Utah's night beyond the arc against Duke in the Sweet 16. The Utes shot 4 of 16 from beyond the arc, while the Blue Devils made 3 of 9.