The fourth-seeded Nishikori reached the quarterfinals last month of the Australian Open and showed in Argentina he can also play on outdoor clay.
In another first-round match, Chile's Fernando Gonzalez, who will retire next month after the Masters tournament in Florida, advanced after Spaniard Albert Montanes retired during the second set with a hip injury. Gonzalez was leading 7-5, 1-0.
Also in the first round, Carlos Berlocq of Argentina defeated Pere Riba of Spain, 6-7 (5), 6-0, 6-0, Victor Hanescu of Romania topped Pablo Andujar of Spain 6-3, 4-6, 7-6 (4) and Facundo Bagnis beat fellow Argentine Leonardo Mayer 5-7, 6-4, 6-2.
The 22-year-old Japanese overcame five double faults to beat the former French Open champion Ferrero.
"He (Ferrero's) been one of the greatest players, so I am really happy to win this," Nishikori said. "I'm not really used it (clay), but I'm trying to play good on clay."
Nishikori moved to the United States at the age of 14 and attended the Nick Bollettieri Academy in Florida. It has paid off. At the age of 18, he won at Delray Beach to became the youngest man to win an ATP title since Lleyton Hewitt captured his first in 1998 at 16.
"I'm feeling really confident. I'm playing well this year and trying to improve my ranking (No. 17)," he said. "If I keep playing like this I have some chance to get to the top."
Gonzalez said he felt sorry for his Spanish opponent, but valued any opportunity to play another match with his career winding down.
"It strange what happened to Albert," Gonzalez said. "But it's good for me. The more times I have a chance to play, the better."