The undefeated Manchester fighter, 26, was awarded a 117-110, 115-112, 117-110 verdict over his Liverpool opponent.
Flanagan was docked a point in the eighth round by referee Phil Edwards for using his forearm, after receiving repeated warnings for pushing.
But it made no difference at the Liverpool Echo Arena as 32-year-old Mathews slipped to a 10th defeat.
Flanagan has now won all 30 of his professional fights.
His promoter, Frank Warren, says "the obvious next fight" for him is against fellow Mancunian and holder of the WBA lightweight world title Anthony Crolla.
"We've made him a big offer," said Warren on Box Nation. "Let the two of them fight. There's no problem from our end. It's a fight that could be made.
"Other than that I like the Linares fight," he added, referring to Venezuelan three-weight champion Jorge Linares, who currently holds the WBC version of the world lightweight title.
Crolla is scheduled to defend his WBA lightweight title against Ismael Barroso at the Manchester Arena on 7 May.
Terry Flanagan retained his WBO world lightweight title with a unanimous points decision over Derry Mathews.