Tennessee (16-4) battled back from 19 points down in the second half but fell 77-67 to Notre Dame (19-1).
The Irish' Skylar Diggins scored a career-high 33 points - besting the 32 tallied last season against West Virginia - and Notre Dame became the first team to beat both Tennessee and Connecticut in the same season for three straight years.
Tennessee lost sophomore post Isabelle Harrison to a left knee injury in the first half - Coach Holly Warlick said the extent of the injury was not yet known - and freshman Bashaara Graves went the distance and put up 19 points and 13 boards, her eighth double-double of the season, which leads the Lady Vols and is second in the SEC.
Taber Spani also reached double digits for Tennessee with 12 points, and Meighan Simmons added 11. Jasmine Jones and Kamiko Williams combined for 16 points off the bench.
Jewell Loyd tallied 10 points for Notre Dame, while Kayla McBride and Madison Cable tallied nine each.
Tennessee gets right back into conference play by hosting Mississippi State on Thursday and then playing at Missouri on Sunday.