The Huskies (31-4) limited Kansas State to 18 percent shooting and 10 field goals in their second-round matchup.
"Defense is what we take pride in here," said Kaleena Mosqueda-Lewis, who added 15 points. "I feel like we have a lot of good offensive players, but it doesn't really take heart to play offense."
UConn, which will play the winner of Penn State and LSU in Kingston, R.I., on Sunday in the regional semifinals, advanced to the round of 16 for the 19th straight season.
Eighth-seeded Kansas State (20-14) was trying to make it that far for the first time since 2002. But the Wildcats were no match for the Huskies, unable to surpass the 27 points that Southern scored against Duke in 2006, the previous record.
Brittany Chambers scored 11 points to lead the Wildcats, who went 11 minutes in the first half without a point.
After taking a 3-2 lead 34 seconds in, the Wildcats missed 18 straight shots over the next 11:17. By the time Jalana Childs put back a miss, they trailed 19-5 with 8:09 left. They could never recover.
Even when Kansas State did something right, it went wrong. Twice the Wildcats had steals at midcourt that would have led to easy layups, but UConn was whistled for fouls. Both times Kansas State took the ball out on the side and was unable to convert the turnovers into baskets.
UConn, which leads the nation in scoring defense at just under 46 points a game and field goal percentage defense (.300), was converting Kansas State's misses into easy baskets.
Hartley and Mosqueda-Lewis outscored the Wildcats in the first half. Mosqueda-Lewis, who matched the UConn record with 21 points in her NCAA debut, fell just five short of the school's two-game mark held by Maya Moore.
The Huskies led, 38-10, at halftime, as the Wildcats missed 27 of their 31 shots.
A late basket by Emma Ostermann gave Kansas State 26 points. The Wildcats had a few chances for more, but couldn't come up with another point.
In other Kingston Regional games:
* At Spokane, Wash., Kayla Standish scored 19 points as 11th-seeded Gonzaga (28-5) upset No. 3 Miami, 65-54, to advance to the round of 16 for the second consecutive season. Shenise Johnson scored 20 points and had 13 rebounds for Miami (26-6).
* At Ames, Iowa, Samarie Walker had 15 points and 13 rebounds to lead Kentucky (27-6) over Wisconsin-Green Bay, 65-62.
Raleigh Regional * At College Park, Md., Laurin Mincy had 24 points, and Maryland (30-4) squeezed past Louisville, 72-68, to reach the round of 16. Shoni Schimmel scored 22 for the Cardinals (23-10). *
At College Station, Texas, Sydney Carter hit the go-ahead free throws with 23 seconds left, Adaora Elonu scored 23 points and Texas A&M (24-10) fought off scrappy Arkansas for a 61-59.
Des Moines Regional *
At Rosemont, Ill., Shekinna Stricklen scored 17 points, and Glory Johnson grabbed a season-high 21 rebounds to lead Tennessee (26-8) past DePaul, 63-48.
Fresno Regional *
At West Lafayette, Ind., Markeshia Grant scored 21 points and fifth-seeded South Carolina beat No. 4 seed Purdue, 72-61. The Gamecocks (25-9) will face top-seeded Stanford in the regional semifinals on Saturday.
* At Norfolk, Va., Amber Orrange scored a career-high 18 points and Stanford (33-1) beat West Virginia, 72-55.
After five seasons of disappointing results and failure to live up to high expectations, Texas women's coach Gail Goestenkors resigned, saying she is "tired" and needs to step away from basketball. Goestenkors, 49, had 2 years left on a 7-year contract paying her $1.25 million per season and she needed to stay only until April 1 to get an automatic 1-year extension. She was 102-64 at Texas and 498-163 overall in 20 seasons as a head coach.