The Friday victory was the 17th consecutive for UC Irvine, which lost 57-55 to Louisville in 2015 in their only NCAA appearance.
The Big West winners were the only team from Southern California to qualify for the tournament.
The leading scorers for the Anteaters were Max Hazzard and Evan Leonard. Each scored 19 points.
Consecutive 3-pointers from Leonard was a deciding moment in the game and helped seal one of the biggest upsets of the tournament so far.
The win is the school's first in the tournament.
#Breaking— Curt Sandoval (@abc7curt) March 22, 2019
UC Irvine wins it’s first #NCAA tournament game in school history!
The #13 seeded Anteaters stun#4 seed Kanas State 70-64!
#UCI wins it’s 17th straight game!
UC Irvine now advances to the second round of the South Region for a matchup against Oregon on Sunday.
The Associated Press contributed to this report.