The matches will be held from September 18-22 in the Sharjah Cricket Stadium and will follow Afghanistan's one-off Test match against New Zealand, which has been scheduled for September 9-13 in Greater Noida, India.
"The recent International Cricket Council meeting was quite productive for us," Afghanistan Cricket Board chairman Mirwais Ashraf said.
"Apart from confirming dates for the one-off Test match against New Zealand, we reached an agreement with Cricket South Africa for a series of three ODIs in September.
"... They're an excellent team, and we are eagerly looking forward to hosting them and playing them regularly in future."
Afghanistan, who boast star allrounder Rashid Khan, and South Africa have played twice in ODIs, with both matches coming in World Cups in 2019 and 2023.
The teams have also met three times in T20 World Cups, in 2010, 2016 and the semi-finals of this year's edition, with the Proteas winning each time.
"We're excited to embark on this historic ODI series with Afghanistan, who have become a very competitive all-round team as evidenced by their recent performances," said Cricket South Africa chief Lawson Naidoo.
"This is a significant milestone in our cricketing relations, and we look forward to a competitive and entertaining series."
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