Batters Aiden Markram and David Miller have been rested for the first two matches while pace bowling pair Kagiso Rabada and Anrich Nortje will also be sitting out.
To make matters, Wiaan Mulder was forced to pull out out of the squad with a side strain while Sisanda Magala split the webbing between his thumb and index finger on his right hand at training.
Ryan Rickelton, Tristan Stubbs, Tony de Zorzi and Gerald Coetzee could make their ODI debuts with captain Temba Bavuma insisting that winning is still the Proteas' main priority.
"The priority will always be to win the series but there will be an effort to widen the pool and give guys opportunities," Bavuma told reporters.
"We'd like to see where they will fit in with our plans moving forward."
The series against the Windies falls outside World Cup qualification bracket but it is the first under new white-ball coach Rob Walter.
The Proteas beat world champions England in the 50-over format in January and it is now the ideal time to give some players opportunities ahead of the World Cup later this year.
Bavuma added: "You want to keep the good thing going and with that said, we can't ignore the fact that it's a big year from a 50-over perspective.
"We still want to win the series, but it's even better when you have the new faces come in under pressure and uncertainty, from where they put in the winning performances.
"There are guys who weren't involved in the Test team, and they come with a lot of hunger and they'd also like to be among the star performers."