The 26-year-old missed the narrow victory at home against title rivals Chelsea last weekend due to fitness concerns, but he has since returned to training and will be in contention to feature at St Mary's.
However, Oleksandr Zinchenko is ruled out with a knock, while Cole Palmer remains doubtful due to a lack of fitness, but otherwise, Guardiola has no other selection concerns, with another strong starting lineup set to be named this weekend.
Ruben Dias watched on from the substitutes' bench against Chelsea but the Portugal international could return at centre-back at the expense of John Stones, joining Kyle Walker, Aymeric Laporte and Joao Cancelo in the back four.
Kevin De Bruyne, who has assisted in all three of his league starts at St Mary's (four in total), will likely join Rodri and Bernardo Silva to form a formidable three-man midfield, though Ilkay Gundogan will be desperate to start having been benched in each of City's last three league games.
In attack, Gabriel Jesus could return to the first XI, which would likely see either Jack Grealish or Raheem Sterling drop to the bench; the latter scored the only goal in a 1-0 win at St Mary's last season.
Manchester City possible starting lineup: Ederson; Walker, Dias, Laporte, Cancelo; De Bruyne, Rodri, B. Silva; Jesus, Foden, Sterling