Litrell started his coaching as a graduate assistant for the Kansas Jayhawks football team for two seasons from 2002 to 2004.
Under Mike Leach, he was running backs coach at Texas Tech from 2005 to 2008. From 2009 to 2011, Littrell coached the offense at Arizona. Then from 2012 to 2013, Littrell was offensive coordinator and tight ends coach at Indiana from 2012 to 2013. From 2014 to 2015, Littrell was assistant head coach for offense and tight ends coach at North Carolina under Larry Fedora. In Littrell's last season at North Carolina, the team finished 11–3 and first place in the ACC Coastal Division.
On December 5, 2015, Littrell was named the head coach at North Texas. UNT hired Littrell after the Mean Green finished 1-11 in 2015. School officials moved quickly to sign Littrell to an extension following the season through 2021.. After his first season which saw the team finish in a bowl game and with a 5-8 record, his second season his team broke through. With great play from future NFL back Jeffrey Wilson, senior Kishawn McClain, and the future program passing leader sophomore Mason Fine, the team finished the season with a 9-5 record. This was the first 9 win season in almost 40 years for UNT and led to another contract extension. The following season Seth Littrell led the Mean Green to a 4-0 start with wins that included a 46-23 win over rival SMU, and a surprising 44-17 win over SEC Arkansas. The team finished again with 9 wins and a third consecutive bowl appearance. Seth Littrell is 0-3 in bowl games with the most recent game coming on December 15, 2018 where UNT lost to Utah State 52-13.