Granollers, ranked 44th, fought back for a 4-6 6-4 6-4 win on the Tokyo hard courts as Ferrer's hopes of qualifying for the ATP World Tour Finals in November took another knock.
Ferrer also lost in the first round of the Shenzen Open last week to Viktor Troicki and is currently seventh in the ATP Race standings with the top eight qualifying for a place in London.
Ninth-placed Milos Raonic and 11th-ranked Jo-Wilfried Tsonga open their Japan Open accounts on Tuesday as they look to pick up precious points to put the heat on Ferrer.
It was a first win for Granollers over his compatriot in six attempts and his reward is a second-round match-up with American Steve Johnson, who served 12 aces in dispatching local qualifier Hiroki Moriya 7-6(4) 6-2.
Home hopes in Japan rest with U.S. Open finalist Kei Nishikori, who begins his campaign later in the week against Croatia's Ivan Dodig.
Nishikori, who became the first Asian man to reach a grand slam singles final in New York earlier this month, won last week's title in Malaysia to move up to a career best seventh in the world rankings.
(Writing by Patrick Johnston in Singapore)
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