Mendy is the club's most expensive new addition this season so far, having joined from AS Monaco in a £49.3m deal last month, but has been on the sidelines ever since with a troublesome thigh injury.
Guardiola previously revealed that the defender has been battling with the problem for the last eight months and he has now confirmed that he and German midfielder Ilkay Gundogan will miss tomorrow night's trip to the south coast.
"No [Mendy and Gundogan are not fit]," he told reporters. "I think soon [they will be back] but not for this game.
"My experience of being a manager, always the beginning of the season the new ones are the toughest ones.
"We spoke and I saw last season how tough is this league. The teams that arrive, in the first four, five, six games they are so complicated. But we try to win the game."
After facing Chris Hughton's side, City face Everton (H), Bournemouth (A) and Liverpool (H) in their next three fixtures.