Second seed Ferrer lost in his first match at the Shenzhen Open last week to Viktor Troicki and he let a one-set lead slip away on Monday as Granollers recorded a 4-6 6-4 6-4 victory.
Ferrer had previously won all five of the pair's meetings on Tour and, having saved three break points on his own serve in the opening set, it was the world number five who converted the only opening he was able to create in the 10th game of the match.
However, it all went downhill from there for the 2007 champion as Granollers won five successive games at the start of the second before holding on to level the match with 54 per cent of the points.
Both players started the decider well but Ferrer lost his serve in successive games in the middle of the set as his hopes of making the end of season finals in London took another blow.
Another seed, Alexandr Dolgopolov, also struggled in the first round of the ATP 500 hard-court event as American Jack Sock completed a 6-4 6-1 win in just 54 minutes.
Sock only dropped five points on his serve in the opening set as his eighth-seeded opponent struggled to make any headway, while the AMerican was able to convert both his break chances.
As Dolgopolov looked to get himself back into the match he took the opening game of the second but he promptly lost the next six, including three breaks of serve, to drop out of the competition.
Seventh seed Kevin Anderson had no problems, though, as he completed a straight sets win over Dominic Thiem.
Having traded breaks in the opening set it was Anderson who held his nerve in the tie-break to convert the solitary opening on his way to a 7-6 (7-5) 6-4 victory that included 11 aces.
Steve Johnson's serve also helped him overcome local qualifier Hiroki Moriya as he fired down 12 aces on his way to a 7-6 (7-4) 6-2 win, while Gilles Muller for 56 per cent of the points in his 6-3 6-4 victory over Federico Delbonis.
Meanwhile, Andrey Golubev saved eight break points on his way to a 6-4 6-4 win against Pierre-Hugues Herbert and Denis Istomin sent Japanese wildcard Taro Daniel to a 7-6 (7-2) 6-7 (5-7) 7-5 defeat.