Early attacks by Henrique Viana and Regan Coldicott threatened the goal but determined defence and good goalkeeping looked set to keep United scoreless.
Milos Nikolic opened the scoring from the penalty spot for Waikato-BOP in the 31st minute, when referee Anthony Riley punished a rash trip on Liam Higgins by centreback Peter Overmire.
Shortly after, Higgins and Jacob Schneider clashed heads in a bloody encounter, but both played on, and Southern coach Luiz Uehara eventually gave most of his travelling squad a run in what was another frustrating match for United.
Just as thoughts were turning to halftime, Waikato-BOP's Mark Jones delivered a quality cross that Shaydon Young headed past keeper Tom Batty, to dampen spirits at the break with a 2-0 scoreline.
At the restart, Southern looked refreshed and should have made more of a clever flick-on by Matt Joy, who used his height at an attacking freekick.
Geordie Mansford turned defenders and delivered a good quality cross that had Waikato-BOP scrambling, but that was the flying winger's last involvement.
On the hour, Uehara gambled on three rapid substitutions, benching Mansford, Coldicott and Aajay Cunningham, and bringing on Nick Hindson, Taylor McCormack and Andrew Ridden.
However, it was a Waikato-BOP substitute that had immediate effect as teenager Reid Drake went on and fired an unstoppable 30m shot past Batty, and at 3-0 down, things looked grim for United.
The game opened up, as Ridden shot over the crossbar, keeper Batty had to make a string of saves, and a run by Hindson earned Southern a penalty.
Despite keeper Andy McNeil blocking the initial spot kick, Viana laced in the rebound to narrow the score to 3-1 after 72 minutes. McCormack then drilled a shot goalwards as Southern kept fighting.
Disappointingly, it was a Waikato-BOP corner that killed the match as Drake launched a corner and the unmarked Nikolic scored his second goal for a 4-1 scoreline with five minutes to go.
Sparking until the end, Ridden used pace to deliver a quality cross that Joy rammed past the former Scottish professional keeper, but not for the first time this season, it was too little, too late for United.
Southern United, on an 11-game losing streak, now has a week off, before another stiff away encounter against the youth side, Wanderers, on December 22.
ASB Premiership
The scores
Waikato-BOP 4
Milos Nikolic 2, Shaydon Young, Reid Drake
Southern United 2
Henrique Viana, Matt Joy
Halftime: Waikato-Bop 2-0.
