The lively Leroy Lita took advantage of some casual defending to tap in the opener from Glen Little's cross.
Kevin Doyle made it 2-0 before the break, brilliantly controlling Marcus Hahnemann's long clearance and fizzing a low shot into the bottom corner.
Saints had their chances, notably Richard Chaplow who hit the bar with a header, but the Royals eased home.
Southampton manager George Burley:
"I was happy with the work-rate because we matched Reading and they play at a very high tempo.
"I have had to restructure squads at Ipswich, Derby and Hearts but this is the most drastic with 17 players having gone out already.
"When the summer comes, I hope to get some more permanent signings in. We tried in January but only managed to bring Alexander Ostlund in on a permanent basis."
Reading: Hahnemann, Murty, Sonko, Ingimarsson, Shorey, Little, Sidwell, Harper, Convey (Hunt 81), Lita (Kitson 76), Doyle.
Subs Not Used: Oster, Stack, Gunnarsson.
Goals: Lita 16, Doyle 38.
Southampton: Bialkowski, Ostlund, Lundekvam, Powell, Higginbotham, Potter, Wright, Chaplow, Dyer (Surman 70), Rasiak, Madsen (Jones 81).
Subs Not Used: Smith, Baird, Blackstock.
Booked: Ostlund.
Att: 23,845
Ref: A D'Urso (Essex).