Sams' TDs came on a 1-yard rush and a 5-yarder, and Waters scored from 1 yard and 13 yards.
Waters threw a 20-yard touchdown to Tramaine Thompson. John Hubert, who scored on a 63-yard run early in the game, finished with 157 yards on 23 carries to lead the Wildcats.
Ty Zimmerman scored a 43-yard touchdown after intercepting a pass from Texas Tech backup quarterback Baker Mayfield early in the fourth quarter.
The win was the third in a row for the Wildcats (5-4, 3-3 Big 12), while the Red Raiders (7-3, 4-3) dropped their third straight game.
Mayfield, who came in for starter Davis Webb late in the second quarter, was 34 for 44 for 276 yards and two interceptions.
Waters was six of nine for 65 yards passing. He rushed for 38 yards on eight carries. Sams finished with 81 yards on 11 carries.
The Wildcats put the game out of reach when Mayfield was intercepted for the first time at Texas Tech's 43-yard line and Zimmerman returned it for a score less than a minute after a previous
Texas Tech slowed
Tyler Lockett led the Wildcats in receptions, getting 44 yards on four receptions.
The Wildcats got just 48 yards rushing in the third quarter and the bulk of those came on a key third-and-5 at the Red Raiders 30-yard line following an unsuccessful onside kick by Texas Tech. Sams started right but juked back left and went for 27 yards and a first down. Two plays later, on the first play of the fourth quarter, Sams scored from a yard out to put the Wildcats up 42-19.
On the Wildcats' second play from scrimmage, Hubert ran left and scampered untouched along the far sideline for his 63-yard touchdown.
Eric Ward led Texas Tech with 11 catches for 107 yards.
Red Raiders receiver Jace Amaro, the Big 12's leader in receptions, continued his streak of games with at least eight catches. He finished with nine for 67 yards.
Mayfield's interceptions was his sixth and seventh of the season and Waters converted the backup's fumble into a touchdown when he found Thompson in the end zone.
Starting Texas Tech quarterback Davis Webb was 13 for 20 for 78 yards and a touchdown before going out.