Cambiasso, who has been capped 52 times at international level by Argentina, is expected to quit Inter Milan when his contract expires at the end of the season.
He first left River for Europe in 2002, and D'Onofrio has admitted that he would love to bring Cambiasso back to the club, but has revealed that the 33-year-old has already settled on a switch to America.
D'Onofrio told Telam: "I would really love to bring him back here, but I can say with certainty that, when Cambiasso leaves Inter, he will continue his career in the United States."
Cambiasso spent two years at Real Madrid before moving to Inter in 2004. He has since made over 300 appearances for the Italian giants, winning five Serie A titles and the Champions League.