Of the total of weapons reported lost or stolen between March 2008 and March this year, only 565 have been tracked down, the minister said in a written reply to a parliamentary question.
South Africa has one of the world's most violent societies, with nearly 50 killings a day, which has fuelled debate over safety at Soccer World Cup that kicks off next week.
The highest firearm losses were in the impoverished Eastern Cape, where 1 708 guns went missing.
Fifty-six police officers had been charged in connection with the losses and 33 had been found guilty so far, said Mthethwa, who has asked the police civilian secretariat to look into the issue.
"We will no longer tolerate such negligent behaviour," he said.
These are the same Police who deny us firearm licences and throw the book at you if your firearm is stolen. I think there is a roaring black market for police guns and certain members are probably cashing in as there is no other way how 5300 guns go missing without explanation over a one year period?