Kevan Hurst handed Southend the lead four minutes before half-time but the hosts could not hold out.
Oxford stay top despite scrambling to a 1-1 draw at Fleetwood.
Stephen Schumacher's 12th-minute strike put the home side ahead and Oxford then squandered a chance to level when former Fleetwood man Danny Rose saw his penalty saved by Scott Davies.
But Dave Kitson struck in the 89th minute to earn a share of the spoils.
Scunthorpe's 3-1 victory over Torquay sends them to fourth, with the Devon side falling to the foot of the table.
Northampton's 1-0 win over Accrington took them off the bottom of the standings, thanks to Stuart Dallas' goal.
David Clarkson, Tom Parkes and Matt Harrold hit unanswered goals in Bristol Rovers' 3-0 home victory over Wimbledon, while Dagenham and Redbridge eased past 10-man Wycombe 2-0 through goals from Afolabi Obafemi and Rhys Murphy.
Wycombe played almost the entire second half with a man less after Anthony Stewart was sent off.
Exeter and Bury shared a 2-2 draw, Tom Nicholls coming off the bench to grab a 77th-minute equaliser for the Grecians.
Daniel Nardiello and Nathan Cameron scored for Bury, sandwiching a leveller from David Wheeler .
Hartlepool and Portsmouth shared a goalless draw, while Jack Redshaw and Kevin Ellison overturned Mansfield's early lead to hand Morecombe a 2-1 win on the road.
Ross Dyer gave the home side the lead on 17 minutes, before Redshaw levelled and Ellison struck the winner five minutes from time. Sam Clucas missed a 75th-minute penalty for Mansfield that would have put them back in front.
Adam McGurk netted an early winner for Burton in their 1-0 triumph at Plymouth while York held high-flying Rochdale to a goalless draw at Bootham Crescent.