The 27-year-old from Argentina was playing in an ATP 500-level final for the first time in his career and showed his battling qualities to claim a 6-7 (3-7) 6-1 7-6 (7-4) win on the clay courts in Germany.
Top seed Ferrer was playing his 44th ATP final and 11 of his 21 titles have come on the red surface, but he was unable to add to his impressive haul in a thrilling encounter.
Mayer, who beat home favourite Philipp Kohlschreiber in straight sets in the semi-final, took the early initiative when he broke in the first game.
Ferrer, ranked seventh in the world, levelled the set in the sixth game and there was a break apiece before it went to a tie-break.
In the breaker it was Spaniard Ferrer whose quality told as Mayer lost a set for the first time in the tournament.
Undeterred by the setback, Mayer roared back with a superb second-set showing, breaking on two occasions and winning 76 per cent of first-serve points in the second set.
Mayer continued his momentum in the decider by breaking for a 3-2 lead in the fifth game, but his nerve failed him when he had the chance to serve for the win at 5-4.
However, he got another opportunity in the tie-break and when a huge ace - his 10th of the match - brought up match point he followed with a big serve and a thunderous half volley before sinking to his knees in celebration.