A large fire engulfed a building in the vicinity of St Mary's, before fire-fighters travelled to the scene to try to contain the flames while a long column of smoke stretched high into the sky.
With the Championship match due to kick-off tonight, the EFL quickly met with the two clubs and opted to postpone the game.
A new date has not yet been announced, but Southampton have guaranteed that tickets will remain valid.
"The incident has caused significant disruption in the area with road closures around the stadium still in place as fire crews continue to deal with the situation," said a release by the Saints.
"We are grateful for the cooperation of Preston and the EFL, and while we appreciate the disappointment fans may feel, we hope they will understand the need to put the safety of supporters and staff of both clubs first.
"The game will be postponed to a new date, which will be announced in due course, and all tickets for tonight’s match will be valid for the rearranged fixture."
