Two goals from Leon Constantine and headers from Drewe Broughton and Leon Cort secured a 4-2 win to move them up to 13th in the table.
Three months ago they looked certainties for relegation but this victory extended their unbeaten league run to eight matches.
Meanwhile, the result leaves Scunthorpe in danger of relegation to the Nationwide Conference. They are now 17th but only six points off the drop-zone and have played at least one game more than the teams below them.
That was the only game this evening. Hull City have the chance to go top tomorrow if they get a result at Kidderminster and leaders Doncaster slip up against Bury at Belle Vue. 3rd-placed Huddersfield are at Leyton Orient, while Torquay and Oxford face tough games against Yeovil and Northampton respectively.
Click here to see FootyMad's full report on Scunthorpe's defeat at Southend or click here to see the current league standings.