China-based Ighalo, who plays for Changchun Yatai, is the leading scorer in the Africa Cup qualifiers with six goals.
But a hamstring injury that has sidelined him for five weeks means Onyekuru comes off the standby list to take his place in the Super Eagles squad, said the Nigeria Football Federation (NFF).
NFF spokesman Toyin Ibitoye said he expects the players who will replace key absentees like Ighalo, Shehu Abdullahi, Francis Uzoho and Wilfred Ndidi to rise to the occasion.
“It’s a massive blow to be without a player who has scored six goals in the last three matches for the Eagles,” Ibitoye said.
“So it’s a big challenge to fill this role, but we have a lot of options in this regard and it is left for the other players to rise to the occasion.
“Other players need to prove themselves worthy to the coaches and Nigerians that they can do it.”
Group E leaders Nigeria face second-placed South Africa on November 17 in Johannesburg.
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