The 27-year-old Orlando Pirates goalkeeper suffered a single shot through the chest during the incident at the home of Kelly Khumalo, a local actress and singer.
“Two guys entered the house and demanded cellphones, money and other valuables,” provincial Community Safety MEC Sizakele Nkosi-Malubane told reporters at the scene.
“Senzo tried to protect Kelly because one of the men had a gun pointed towards her.”
Police said two men entered Khumalo’s house in Vosloorus at about 8pm. A third waited outside the house and all three fled immediately after the shooting.
Meyiwa was declared dead on arrival at hospital, the police added.
South Africa’s national team coach Ephraim Mashaba comforted several of Meyiwa’s teammates who were at the hospital not long after the shooting.
“We can assure all South Africans that we will do all we can to bring Meyiwa's killers (to) book,” the South African Police Service said on its Twitter account. Police are offering a R150,000 reward for information that can lead to an arrest.
The 27-year-old captained South Africa in their last four matches in the African Nations Cup qualifiers without conceding a goal and played on Saturday when his club advanced to the semi-finals of the Telkom Knockout.
“This is a sad loss which ever way you look at it – to Senzo’s family, his extended family, Orlando Pirates and to the nation,” Pirates chairman Irvin Khoza said in a statement.
News of the shooting prompted widespread sympathy on social media and condemnation of South Africa’s rampant gun violence.
“How do you kill someone for a cellphone?” tweeted national team mate Tsepo Masilela.
Belgian-based goalkeeper Darren Keet, who had been Meyiwa’s understudy over the last four internationals, tweeted: “When does it STOP South Africa?”
“We are deeply saddened but shouldn’t we be angry too? When is it going to be stopped? Crime won’t stop by itself, we need leadership,” added South Africa’s Premier Soccer League general manager Derek Blanckensee.
More than 17,000 people were murdered in South Africa between April 2013 and March 2014, an increase of about 800 over the previous year, according to police figures.