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 Fleetwood looked primed for victory, until Dave Kitson struck in the 89th minute.
Scunthorpe's 3-1 victory over Torquay sends them to fourth, with the Devon side falling to the foot of the table.
Sam Winnall, an own goal from Anthony O'Connor, and Hakeeb Adelakun put Scunthorpe in charge and meant John Marquis' late strike was a mere consolation for Torquay.
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 Exeter.
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.