Van Gaal said on Friday that Rooney would return from the knee injury that ruled him out of Wednesday's 2-1 home win over Stoke City.
The United captain and Dutchman Van Persie have enjoyed a lot of success against Southampton in the past and may team up again, although Van Gaal can also call upon fit-again Colombia forward Radamel Falcao.
Rooney has struck five goals in as many starts for United against the south-coast club and Van Persie has also scored five against them including a hat-trick at St Mary's two years ago.
Third-placed Southampton have lost their last two games, against Manchester City and Arsenal, but Van Gaal believes they can wind up in the Champions League qualifying positions at the end of the season.
"They have a very good squad," the Dutchman told a news conference on Friday.
"I think they are able to finish in the first four but that's also because I believe in the manager, in Ronald Koeman. I believe the cohesion there is good."
The pair were involved in a high-profile bustup when they were at Ajax Amsterdam a decade ago.
"My relationship with Ronald Koeman doesn't have to be described, that's private," said Van Gaal.
"We play against Southampton and we should talk about the team rather than the coach. After the game we can reflect on the relationship."
United, one point behind Southampton in fourth spot, will be without Argentina winger Angel Di Maria because of a hamstring injury.
(Editing by Tony Jimenez)
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