Kentucky hosts Notre Dame on Dec. 12 in the first regular-season meeting between the schools since Notre Dame's 64-50 victory at home on Nov. 29, 2012.
The teams will play at a neutral site to be determined on Dec. 11, 2021, and the Wildcats will visit the Fighting Irish on Dec. 10, 2022.
"It is great to renew a series between two of the 'blue bloods' of college basketball," Notre Dame coach Mike Brey said on the school's website.
Kentucky is 43-19 against Notre Dame all time, including 8-0 at home, and won the previous meeting 68-66 in a tense 2015 NCAA tournament regional final in Cleveland.
The Wildcats are 10-6 in South Bend, though the Irish have won the past two at home.
"If our previous games are any indication, this is going to be a great series," Kentucky coach John Calipari said in a release.