Of Portuguese ancestry, Valdés Leal was born in Seville in 1622. Little is known about his early life, but by his twenties he studied in Córdoba with painter Antonio del Castillo and started his own workshop. His artistic influences were probably Italian (Tintoretto, Titian) as well as his contemporaries from Madrid and Seville.

Even during his lifetime, Juan de Valdés Leal became known for somber, if not macabre, subjects painted in a dramatic style. (See "In Ictu Oculi" as an example of his work in Seville's Hospital de la Caridad) Commissions throughout his life included altarpieces, retables, vanitas paintings, and frescoes. Valdés Leal's art reflects the intensely religious spirit of seventeenth-century Spain, which he inventively heightened by using exotic colors, dramatic light, and lively brushwork.

Valdés Leal married in 1647 and had five children. His wife (daughter of artist Antonio Palomino), Isabella Carasquilla, was also a painter. She died in Seville as late as 1730. Their children were artists, including Lucas, Juan, Maria, and Laura de Valdés. His daughters specialized in portrait miniatures. Maria died a nun in the Cistercian monastery in Seville, in 1730.

Valdés Leal's art developed as the antithesis of the dominant artist of that region and period, Bartolomé Esteban Murillo, whose style was by contrast, serene and sweet. Yet the two artists became friends and often worked together on large commissions. After Valdés Leal returned to Seville in 1656, he helped Murillo found the Seville Academy of Art. He, Murillo, and Pedro Roldán worked together on a large commission for Seville's Hospital de la Caridad (Hospital of Charity). In addition to painting and drawing, Valdés Leal also worked as a sculptor, printmaker, and gilder. After 1680, he worked primarily in fresco. Later in life, his son Lucas assisted and collaborated with him.

Among his works are the retablo or altarpiece, containing a variety of pictures, for the church of the Carmelites; a Martyrdom of St. Andrew for the church of San Francesco in Córdoba; and a Triumph of the Cross for la Caridad in Seville. He was one of the founders of the Seville Academy along with his friend.