Webb was 35 for 56 with an interception, and Kenny Williams, Deandre Washington and Sadale Foster each ran for a score for Texas Tech (6-0, 3-0 Big 12). The Red Raiders are bowl eligible at their earliest date since 2008 in their first season under coach Kliff Kingsbury.
The Cyclones (1-4, 0-2) got a 95-yard kickoff return for a touchdown from Jarvis West and 12 points off three turnovers by the Red Raiders.
The Cyclones pulled within 42-35 on a touchdown pass from Sam Richardson to E. J. Bibbs with less than 2 minutes left. Richardson was 15 for 38 for 168 yards and a touchdown.
Mayfield twisted his right knee in last week's win at Kansas.
The Red Raiders finished with a season-high 251 yards rushing, with Washington, Williams and Foster each gaining at least 80.
Jace Amaro caught nine passes for 143 yards.
It was the first time in 25 games that the Cyclones allowed an opponent to score more than 40 points. That was the longest active streak in the Big 12.
Texas Tech went up for good in the third quarter on a 12-yard touchdown catch by Bradley Marquez.
After Marquez's touchdown, the Red Raiders appeared to score again on a fumble return by Sam Eguavoen after Richardson lost the ball at the Cyclones 35. But officials reviewed the play and ruled Richardson was attempting a side-arm pass.
Iowa State had just 139 total yards at halftime, to 354 by Texas Tech. But big special teams plays kept the Cyclones in the game.
West returned a kickoff 95 yards for a touchdown midway through the first quarter. It was the first non-onside kick return for a touchdown for Iowa State since 1994.
In the second quarter, an Iowa State punt hit Texas Tech's Keenon Ward downfield. It was recovered for the Cyclones by Levi Peters, and a few plays later Aaron Wimberly scored on a 4-yard run off the option pitch from Richardson to make it 14-14.