Stafford went 23-for-39 through the air for 294 yards and an interception for the Lions (2-0), who racked up their largest margin of victory since a 44-7 win over Denver in 2007.
Calvin Johnson grabbed a pair of scoring strikes and Jahvid Best added rushing and receiving touchdowns as Detroit won its sixth straight game dating back to last season.
On defense, the Lions caused six turnovers, including takeaways on three straight Chiefs possessions in the second half.
Matt Cassel couldn't find the range Sunday, going just 15-for-22 for 133 yards with three interceptions while losing a fumble for Kansas City (0-2), which has been outscored 89-10 in its first two games of the season.
The Chiefs also lost running back Jamaal Charles to a knee injury early in the game.