Antolin Alcaraz, Maynor Figueroa, Franco Di Santo and Ronnie Stam will all leave Wigan on free transfers when their contracts expire in the summer.
Manager Roberto Martinez confirmed the departure of the quartet, saying talks about new deals had broken down even before the FA Cup winners were relegated to the Championship.
“All of the players who are out of contract, we have had conversations over the season and every one made their position clear and we have always been well alerted,” said the Spaniard. “At the moment it's a case of bringing in fresh players, fresh blood.”
Centre-back Alcaraz, 30, arrived on a free transfer from Bruges in 2010 and has been a fixture in Wigan’s defence when fit.
The Paraguayan has only made eight league starts in an injury-hit season but scored the goal that ensured Athletic’s survival last year and helped them keep a clean sheet in Saturday's FA Cup final win over Manchester City.
Left back Figueroa, also 30, has played 199 times for Wigan since joining in 2008. The Honduras international missed the FA Cup final with a groin injury and is expected to join West Ham this summer.
Striker Di Santo, who arrived from Chelsea in 2010, was Wigan’s top scorer last season but only managed 13 goals in 97 games for the club. The Argentine is thought to interest West Brom.
Dutch right-back Stam, a £2 million signing from Twente in 2010, has made 73 appearances for Athletic but has been a fringe player in recent months.
Martinez revealed Wigan are yet to receive an offer for players who are under contract, with Premier League clubs likely to target James McCarthy, Shaun Maloney and Callum McManaman.
“They have been very respectful in that way,” he added.