Stafford overcame a pair of interceptions early in the game to finish 28-of-36 through the air for 335 yards and Kevin Smith ran for a career-high 140 yards with two touchdowns for Detroit (7-3).
Smith added 61 yards and a score on four receptions as the Lions notched their second win in three games.
Carolina (2-8) couldn't overcome four pick-offs surrendered by Cam Newton, who completed 22-of-38 passes with a touchdown.
DeAngelo Williams racked up 105 offensive yards as the Panthers dropped their third straight.
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