Ferrer overcame Lukas Rosol of the Czech Republic 6-0, 2-6, 6-3, while Isner beat Polish qualifier Michal Przysiezny 7-6 (3), 4-6, 6-3.
Rosol hit 19 winners to only 10 for Ferrer, but the Spaniard made 18 fewer unforced errors.
A semifinalist two years ago, Isner broke for 3-1 in the last set when Przysiezny netted a routine volley. The American cracked 27 aces and 47 winners. Isner will next face second-seeded Novak Djokovic.
Roger Federer just needs to win his opening match against Kevin Anderson of South Africa later Wednesday to qualify for the ATP Finals for a 12th straight year.
Tenth-seeded Milos Raonic of Thornhill, Ont., was scheduled to play Dutch qualifier Robin Haase in a late match. In doubles play, the seventh-seeded duo of Toronto's Daniel Nestor and India's Leander Paes were to meet American Scott Lipsky and Mexico's Santiago Gonzalez.