Two men are in police custody, the South African Press Association reported: one is said to be a university professor, another is identified simply as a 25-year-old.
They are accused of vandalizing the picture, titled 'The Spear,' at the Goodman Gallery in Johannesburg this morning.
According to SAPA, a third man was also arrested for attempting to spray paint the word "respect" onto a wall near the artwork.
The incident was caught on camera by a local TV crew, whose footage shows a middle-aged white man painting a red cross over Zuma's face. A younger black man covers the rest of Zuma's body with black paint, before being restrained by a security guard who at one point headbutts the suspect and tackles him to the ground.
"I'm doing this because the painting is disrespectful to President Zuma," one of the men told the BBC's correspondent, who witnessed the attack.
The work of artist Brett Murray, the depiction of Zuma showing his naked genitals was under threat of removal after the ruling ANC party went to court to have it taken off display.
The $14,000, 1.85 meter-high painting was described by its creator as "an attempt at humorous satire of political power and patriarchy" that was never intended "to cause any hurt or to harm the dignity of any person," IOL News quoted Murray as saying.
President Zuma, however, said it was "an undignified depiction of my personality and seeks to create doubt about my personality in the eyes of fellow citizens, family and children."
The ANC's request to have the Goodman Gallery remove the painting from its display, website and promotional materials received a first hearing this morning, the BBC reported, and is due to go before a full bench of the High Court on Thursday.