Preston opened the scoring in the 11th minute when Grimsby goalkeeper Danny Coyne was adjudged to have brought down Preston's Northern Ireland striker David Healy in the penalty box as he ran down the right following a Paul Groves mistake.
Graham Alexander scored from the penalty spot sending the Grimsby goalkeeper the wrong way for his sixth penalty and seventh goal of the season.
Richard Cresswell, back from suspension, scored Preston's second goal in the 26th minute - his 11th goal of the season.
Another mistake by Groves fell to Cresswell who dribbled past four defenders on the right-hand side and scored from seven yards.
The fourth official signalled one extra minute and Preston had Eric Skora stretchered off with a bruised angle but Preston went in 2-0 up at half time.
Groves substituted himself for Terry Cooke and Dickson Etuhu was booked for a foul on Pouton after 57 minutes.
Healy made it 3-0 when he hooked a right-foot shot into the bottom left-hand corner of the net from seven yards after the ball had bobbled round after Cresswell had created the danger.
Mark Rankine came on for Paul McKenna who had a groin injury in the 62nd minute.
Tony Gallimore was booked for dissent in the 68th minute and Healy was booked for a foul on Jason Gavin in the 74th minute.
Grimsby captain Alan Pouton was sent off a minute later for his second bookable offence.