He studied at the University of Salamanca, where he adopted as his own his father's second surname, and later on at the universities of Granada and Alcalá. As a latinist, he translated to Spanish Horace's Epistola ad Pisones.
In 1618, the printer Juan de la Cuesta published Espinel's picaresque novel Relaciones de la vida del escudero Marcos de Obregón. This book, with several autobiographical details, was printed in France the same year and inspired later Lesage's Gil Blas de Santillana. He also published his Assorted rhymes in 1591.
Lope de Vega, who referred to Espinel as his teacher, dedicated him El caballero de Illescas (1602). Espinel also befriended Cervantes, Góngora (whose poetry he helped to publish) and Quevedo. As his friends, he was a member of congregation Esclavos del Santísimo Sacramento. At the time of his death, he was the chaplain at Madrid, and also the music teacher, of the Plasencia bishop.