Francisco Vázquez de Coronado was born into a noble family in Salamanca, Spain, in 1510 as the second son of Juan Vázquez de Coronado y Sosa de Ulloa and Isabel de Luján.

His father had held various positions in the administration of the recently captured Emirate of Granada under Iñigo López de Mendoza, its first Spanish governor.

Coronado had gone to New Spain in 1535 at about age twenty-five, in the entourage of its first Viceroy, Antonio de Mendoza, the son of his father's patron and Coronado's personal friend.

In New Spain, he has married Beatriz de Estrada, called "the Saint" (la Santa), sister of Leonor de Estrada, ancestor of the de Alvarado family and daughter of Treasurer and Governor Alonso de Estrada y Hidalgo, Lord of Picón, and wife Marina Flores Gutiérrez de la Caballería, from a converso Jewish family.

Coronado has inherited a large portion of a Mexican estate from Beatriz and will have eight children by her.

Coronado is from 1538 the Governor of the Kingdom of Nueva Galicia (New Galicia), a province of New Spain located northwest of Mexico and comprising the contemporary Mexican states of Jalisco, Sinaloa and Nayarit.

In 1539, he dispatches Friar Marcos de Niza and Estevanico (more properly known as Estevan), a survivor of the Narváez expedition, on an expedition north from Compostela, in present-day Nayarit, toward present-day New Mexico.