Japan's Nishikori, the tournament's fourth seed, committed five double faults in his match, but also served up four aces and converted on 6-of-14 break opportunities en route to a 7-5, 3-6, 6-2 decision over former world No. 1 Juan Carlos Ferrero of Spain.
Ferrero was the champion at this event two years ago.
Sixth-seeded Swede Wawrinka had it easier, cruising to a 6-3, 6-4 straight-set victory over Argentina's Horacio Zeballos on the red clay at Buenos Aires Lawn Tennis Club.
Wawrinka and Zeballos each recorded four aces and one double fault in the contest, but Wawrinka was able to save 6-of-7 break chances by the Argentinean while converting on three of his four chances to break Zeballos' serve.
In other opening-round play, Romanian Victor Hanescu outlasted Spaniard Pablo Andujar 6-3, 4-6, 7-6 (7-4), Argentina's Carlos Berlocq came back to blitz Spain's Pere Riba 6-7 (5-7), 6-0, 6-0 and Chile's Fernando Gonzalez advanced past Spain's Albert Montanes, who retired with a back injury while trailing 7-5, 1-0.
Also on Monday, Argentina's Facundo Bagnis earned a marathon 5-7, 6-4, 6-2 victory over compatriot Leonardo Mayer in a nearly three-hour long match.
The top seeds here are a pair of Spaniards -- 2010 Buenos Aires runner-up David Ferrer and reigning champion Nicolas Almagro, who also titled in Sao Paulo last week. Almagro beat Argentine favorite Juan Ignacio Chela in last year's Buenos Aires finale.
The 2012 Buenos Aires champion will earn $82,900.