Bradley Wright-Phillips scored twice for Southampton as they ended Reading's unbeaten home record.
The Royals had dropped just two points at the Madejski Stadium this season and nearly went ahead, but Noel Hunt's shot was cleared off the line by Jack Cork.
Wright-Phillips headed in Lloyd James's cross to put the visitors in front, before he blasted a shot across Marcus Hahnemann to double the lead.
Jimmy Kebe pulled one back for Reading after Kevin Doyle's shot was parried.
Reading manager Steve Coppell:
"We never do well after an international break, but I am at a loss to work out why we started so slowly.
"I don't believe we underestimated Southampton because all week I have been stressing that we are not good enough to underestimate anybody.
"They could have scored more, especially in the first half and there were a lot of poor performances from us today."
Southampton boss Jan Poortvliet:
"I am so very proud of what we saw today. Reading are a good team, but we deserved to win.
"In the first half particularly we created a lot of chances and this win will create a lot of confidence.
"Everybody can see what we are capable of. We work on it every day and every week and I think we will be a stronger team next year if we can keep our young players."
Reading: Hahnemann, Rosenior, Bikey, Ingimarsson, Armstrong, Kebe, Harper (Gunnarsson 83), Cisse (Matejovsky 55), Stephen Hunt, Doyle, Noel Hunt (Long 61).
Subs Not Used: Henry, Andersen.
Booked: Matejovsky.
Goals: Kebe 57.
Southampton: Davis, James, Perry, Cork, Skacel, Lallana, Schneiderlin, McGoldrick, Surman, Wright-Phillips, Robertson (Paterson 74).
Subs Not Used: Wotton, Mills, Bialkowski, Gasmi.
Booked: Surman.
Goals: Wright-Phillips 14, 49.
Att: 23,121
Ref: Lee Probert (Wiltshire).
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