Grant gave the Blues the lead from the spot after Bruno Andrade had been bundled over by John McCombe, but the sending off of Jo Kuffour in first-half injury-time changed the complexion of the game.
Substitute Ben Williamson fired the hosts level, before two goals from top scorer Tom Pope put the hosts firmly in control.
Ashley Vincent’s injury-time strike added gloss to the scoreline for Vale, but Wycombe were more than a match until they were a man light.
Gareth Ainsworth named the same starting XI that won 1-0 at Fleetwood Town last Saturday with the only change coming on the bench where fit-again Matt McClure replaced Olly Taylor.
The hosts started well and in the first minute top scorer Tom Pope peeled away from Leon Johnson but could only head Robert Taylor’s far-post cross harmlessly wide.
Wanderers responded well and Dean Morgan curled a free-kick just wide of Chris Neal’s left-hand post after John McCombe had pushed Joel Grant on the edge of the area.
It was a fairly open start and Jennison Myrie-Williams was the next to try his luck after cutting inside Charles Dunne, but he flashed a shot wide from the edge of the area.
The first clear chance came in the eighth minute when Ashley Vincent was played through on goal, but Nikki Bull made himself big and did well to save.
Josh Scowen had Wycombe’s first attempt on goal and it came in the 15th minute when he received the ball from Morgan 20 yards and drilled low, but Neal was equal to it and made a comfortable save.
Ainsworth’s side were enjoying their best spell and were rewarded four minutes later when Andrade was clumsily bundled over by McCombe in the area and Grant made no mistake from 12 yards, firing low to Neal’s right.
Vincent had another opportunity midway through the first half, but again Bull was quick to react and narrow the angle before saving.
Vale enjoyed a lot of the ball in the remainder of the half, but the best chance fell to Scowen who rifled wide from 25 yards.
Blues’ task became harder in injury-time when Kuffour, who was shown a yellow card after an altercation with McCombe earlier in the half, picked up a second caution for a foul on Neal. The keeper made a lot of the challenge, but the referee was quick to send off the Chairboys striker.
Wycombe started the second half brightly despite their numerical disadvantage and Grant was only denied a second by a fine save from Neal. Substitute Matt Spring found Morgan and he in turn played the ball on to Grant on the left.
The winger cut in and curled right-footed, only for Neal to dive full-length to his left and tip the ball over. It would have been a carbon copy of Grant’s strike at Portsmouth had it gone in.
The home side piled on the pressure and their possession was rewarded in the 59th minute when Ben Williamson beat the offside trap and coolly slotted past Bull from just inside the area.
It was 2-1 seven minutes later when Pope rose highest to head home Vincent’s inviting cross from close-range.
Ainsworth brought on Matt McClure as the Chairboys were forced to chase the game and Scowen’s strike was deflected wide before Williamson was off target from Vincent’s clever through ball.
Pope settled any home side nerves three minutes from time with his second, before Vincent added a fourth in injury-time when his strike was saved by Bull, but spun into the net.
Wycombe: Bull, Foster, Dunne, Johnson, Doherty (c), Andrade (Spring 49), Lewis, Scowen (Morias 83), Grant (McClure 68), Morgan, Kuffour.
Subs: Ingram, Winfield, Stewart, Ainsworth.
Port Vale: Neal, Duffy, Taylor, McCombe, McDonald, Dodds, Shuker (James 81), Murphy (Williamson 54), Myrie-Williams (Lloyd 77), Vincent, Pope.
Subs: Johnson, Owen, Davis.
Attendance: 5,303 (232 Wycombe fans)