Michael Egnew, T.J. Moe and Wes Kemp each had a scoring reception for Missouri (3-3, 1-2 Big 12), which scored on its first four possessions. Much of a sellout crowd of 71,004 had dispersed by the end of the Tigers' 10th straight victory at home, and their first game at Faurot Field in a month.
It was the most lopsided setback of the year for Iowa State (3-3, 0-3). A.J. Klein's 78-yard interception return for a touchdown was the lone highlight for the Cyclones, who have been outscored 54-10 in the first quarter.
Iowa State's James White was held to 61 yards on 14 carries a week after getting a career-best 148 yards against Baylor.
White had 10 yards on 10 carries in the first three quarters.
Missouri had no penalty yardage in its fifth straight victory in the series. Linebacker Luke Lambert had two fumble recoveries.
After scoring on the first four drives for a 28-3 cushion, the Tigers turned it over in the passing game the next three times but were hurt only by Klein's third career touchdown. The Tigers had 298 yards rushing one week after managing just 112 yards in a loss at No. 17 Kansas State.
Missouri defensive tackle Terrell Resonno injured his right knee in the first half and did not return. The 295-pound senior has started all 14 games the last two seasons and had 15 tackles and a sack in the first five games.
Franklin was 20 for 28 for 289 yards and three touchdowns and rushed for 84 yards on 11 carries with two touchdowns. Josey had 129 yards on 19 carries for his third 100-yard game of the year and scored in the fifth straight game.
Missouri opened the game with 10 straight runs, including Franklin's 1-yard sneak with 12:03 to go in the first quarter for its fastest first touchdown of the year. The Tigers' second score came quickly, too, after Steele Jantz fumbled on an option run and Lambert recovered at the Iowa State 38, setting up a 2-yard run by Josey.
Egnew had six catches for 105 yards. He split the defense and had an easy route to the end zone the last 20 yards on a 39-yard catch, the longest of the tight end's career, to make it 21-3 late in the first.
The Cyclones lost by 23 points in each of their first two Big 12 games.