"We know that HIV can be prevented and that treatment works," Zuma, a presidential hopeful in next year's elections, told a meeting with religious leaders.
"Therefore, if we act together, we can beat HIV and AIDS within the next 10 years. We must act on the knowledge we have and prevent the disease," he said.
Zuma's call to action is a marked departure from his political rival, former president Thabo Mbeki, who publicly questioned the link between HIV and AIDS while his country was ravaged by the epidemic.
Mbeki's regime was blamed by a recent Harvard study for 365,000 AIDS-related deaths between 2000 and 2005, caused by the failure to implement a timely anti-retroviral (ARV) treatment programme.
Zuma said Thursday that there was renewed commitment from his ruling African National Congress (ANC) and the government "to tackle AIDS head on".
"We know what we should do, and should do it," he said, adding that the disease should no longer be spoken about in "hushed tones."
Mbeki's health minister, Manto Tshabalala-Msimang, was widely discredited for proposing lemon juice, olive oil, garlic and beetroot as AIDS treatments, while arguing against ARVs.
She was recently shuffled to a low-profile post by the country's new leader Kgalema Motlanthe and replaced by Barbara Hogan, whose appointment was welcomed by activists.
Zuma is no stranger to controversy around AIDS.
The populist leader was acquitted for rape in 2006 but faced a stern rebuke from the judge for having unprotected sex and testifying during the trial that he showered after intercourse to avoid HIV.
The South African government now boasts the world's largest anti-retroviral programme but some 5.5 million South Africans are infected by HIV - over 18 percent of the adult population.