The Spaniard started sluggishly at the ATP 500 clay-court event, but recovered to secure a 2-6 6-3 6-2 win.
Kukushkin won 91 per cent of the points on his first serve in the opening set as he barely gave Ferrer a glimmer of an opening, while converting two of the five break points he created.
A stunned Ferrer hit back immediately with the opening two games of the second set and then took advantage as his opponent began to struggle with a leg injury.
With his right leg heavily strapped, the Kazakh's movement was slightly limited, although his forehand still caused problems on occasions.
However, with the match tied at 2-2 in the decider, Ferrer turned the screw to win four consecutive games to progress.
Two other seeds in action on Tuesday also booked third-round spots as Santiago Giraldo and Tommy Robredo both recorded straight-set victories.
Things were not so promising for eighth seed Marcel Granollers as he lost his 13th game on clay this season.
Austria's Dominic Thiem stunned Granollers as he came from a set down to send the Spaniard tumbling out of the tournament 2-6 6-3 7-5.
Having dominated the opening set, Granollers was only able to put pressure on Thiem twice, and the world number 55 comfortably held his serve while breaking his opponent on three occasions.
In the final first-round matches, there were straight-set victories for Alexander Zverev, Jerzy Janowicz, Leonardo Mayer and 2012 winner Juan Monaco.
Meanwhile, Martin Klizan needed three sets to get past Igor Sijsling and Lukas Rosol progressed past Julian Reister after the German retired inured in the second set.