South African police on Monday arrested five suspects over the 2014 murder of national football captain Senzo Meyiwa, a major breakthrough in a case that stunned the crime-ridden nation.

The 27-year-old goalkeeper and national squad captain was gunned down at the home of his pop-star girlfriend Kelly Khumalo, southeast of Johannesburg during the evening of October 26, 2014.

Until now police had failed to find the killers after they reportedly escaped on foot, sparking accusations of incompetence.

A newly-appointed cold case unit took over the sluggish investigation in 2018, gathering evidence that allowed police to make a first string of arrests exactly six years after Meyiwa's murder.

"The first five suspects have been arrested... this morning," police minister Bheki Cele told reporters on Monday.

"Investigations are still ongoing and more arrests cannot be ruled out," he added, lauding the cold-case team for their "tireless" work.

National police commissioner Khehla Sitole said one of the detainees was "the key suspect suspected of having pulled the trigger".

Sitole explained that key ballistic evidence emerged when investigators found the firearm used to shoot Meyiwa and linked it back to the crime scene.

"We have a concrete case this time because it is backed by evidence," he said, noting that the "cracking of the case" had merely coincided with the murder's anniversary.

The five suspects are scheduled to be formally charged in court on Tuesday.

A South African lobby group representing the Meyiwa family praised the arrests and said investigators now had sufficient evidence to show the murder had been pre-meditated.

"We now know it wasn't a robbery went wrong, but in fact an assassination," the head of AfriForum's private prosecution unit Gerrie Nel said in a statement.

"The challenge now is to bring the mastermind behind the murder to justice," said Nel, the former state prosecutor who led the case against Paralympian Oscar Pistorius and has a reputation of winning high-profile cases.

Meyiwa was captain and goalkeeper of both the Bafana Bafana national team and top club Orlando Pirates.

Cele deplored the "immeasurable pain" suffered by the sport icon's family and fans, and vowed to "ensure justice".

Meyiwa's brother Sifiso Meyiwa welcomed the arrests and hoped more would follow.

"We remain anxious that the mastermind was not arrested," he said in a statement.