After taking the lead against Athlone Town last week, Danny Furlong's dismissal made it too hard for Wexford to keep up with a much improved Athlone Town.
Emmet Nugent opened the club's account for the season but just minutes later the side were reduced to ten men and a second half penalty scored by Jack Doherty wasn't enough as Athlone stuck four past Joe Walshe in the Wexford goal.
"We got off to a great start when Emmet scored a good goal, however the game changed for us when we feel Danny was wrongfully sent off," manager Brian O'Sullivan told the club's website.
"It was always going to be an uphill battle after that. When we went 2-1 down we showed good character to get it back to 2-2 but I suppose the second half with the extra man it showed particularly in midfield, they had the majority of possession.
"I felt if we defended the corner (for the 3rd goal) better and hung in for longer we could have got a result with a bit of luck on the night. The fourth goal came from an individual error and completely killed us altogether."
O'Sullivan is looking for a reaction from his players on Friday night for the visit of Galway United.
"We will be looking for better defending from every player all over the pitch and need to make ourselves harder to beat.
"Even with ten men conceding four goals is not good enough. Hopefully tomorrow we can show the fans what we are about. Hopefully we can show energy, passion and a bit of desire with a good performance.
Wexford will be without Chris Kenny through injury, and Danny Furlong also misses out through suspension after his sending off last week.
It was heartbreak in front of a massive crowd last week for The Tribesmen as Shelbourne overturned a two goal deficit late on to deny Galway a shock win on the opening night of the season.
Goals from 17 year-old Colin Kelly and veteran Vinny Faherty set the team up for victory but despite good performances all across the pitch Shels proved too much for the youthful Galway side.
Despite the disappointment, manager Alan Murphy is taking a lot of positives from the defeat into his side's upcoming trip to Wexford on Friday night.
"We fielded a starting eleven with seven under-21 players, that for large portions of the game performed very well and limited Shelbourne to very few chances for the first 75 minutes at least. It's certainly something to build on going into Friday night," he told the club's website.
"It's always a challenge going to Wexford and a long journey on a Friday for the squad. They went ahead against Athlone last week before having a man sent off. That is the sort are thing they will be looking to as a positive from their performance, in spite of losing on the opening night. It probably would have been a very different game but for the dismissal," Murphy explained.
Andrew Peters, Jeff McGowan and Conor Layng are still absent for The Tribesmen through injury but Donal Higgins returns to Murphy's squad following exams.
Wexford haven not beaten Galway since October 2016 when the sides met in Ferrcarraig Park. It was a bizarre game where Wexford went ahead by scoring five goals without reply before Galway scored four in response.
Colin Kelly made his first start for Galway United against Wexford towards the end of last season. The young striker missed a penalty during the game, which finished 1-1.
Only once did either side win in meetings between the two sides last season. The last two games between Wexford and Galway have finished 0-0 and 1-1.
Wexford 11/4; Draw 5/2; Galway United 8/11.
Injured: Andrew Peters, Conor Layng, Jeff McGowan.