Fajardo was the son of a Spanish lieutenant of the same name and an indigenous Indian woman, Isabel of the Waikerí.
As a mestizo (person of mixed race) he was able to blend in with the indigenous tribes of the coast physically and culturally.
[2] He returned to the mainland in 1560, becoming lieutenant-general of Valencia, Venezuela,[2] before going back to Margarita to defend it against Lope de Aguirre.
Early attempts at settlement had to be abandoned in 1562 when an uprising led by Guaicaipuro forced Fajardo to retreat again to Margarita,[2] an expedition by Luis de Narváez to reinforce Fajardo having been destroyed.
After setting out on a new expedition from Margarita in 1564,[2] he was arrested and executed in Cumaná by Alonso Cobos after a sham trial.