Blind from the age of three due to diphtheria, Rodrigo undertook early musical studies under Francisco Antich in Valencia (1920-1923) and Paul Dukas at the École Normale de Musique in Paris (1927-1932). While in Paris, Rodrigo befriended many of the great composers of the time, and received particular encouragement from his fellow Spaniard Manuel de Falla. In 1933 he married the Turkish pianist Victoria Kamhi; they remained inseparable companions until her death in 1997.

After returning to Spain in 1934, Rodrigo quickly won, with some help from Falla, the Conde de Cartagena scholarship that allowed him to return to Paris to study musicology -- with Maurice Emmanuel at the Paris Conservatoire and with André Pirro at the Sorbonne. Some of the most difficult years in Rodrigo's life were in the late 1930s during the Spanish Civil War: his scholarship was cancelled, and he and his wife lived in France and Germany, virtually penniless. They made a meager living giving Spanish and music lessons at the Institute for the Blind in Freiburg. But by 1939, they were able to return to Spain.

Rodrigo started composing in 1923, and won a National Prize in 1925 for his Cinco Piezas Infantiles for orchestra. (Due to his blindness, Rodrigo always composed in Braille, and later painstakingly dictated the music to a copyist.) But his real breakthrough as a composer was with the Concierto de Aranjuez (1940, for guitar and orchestra), which was acclaimed from its first performance in Barcelona. Rodrigo was quickly recognized as one of Spain's great composers, and the awards and commissions started to roll in. In 1947, the Manuel de Falla Chair was created for him at the University of Madrid, where he taught music history for many years. He was much in demand as a pianist and lecturer, traveling to Europe, Central America, the U.S., Israel, and Japan. Many of the world's great instrumentalists commissioned concertos of him, and he eventually wrote works for, among others, guitarist Andrés Segovia, flutist James Galway, harpist Nicanor Zabaleta, and cellist Julian Lloyd Webber.

In 1953, he was awarded the Cross of Alfonso X the Wise by the Spanish government, and as part of the celebration of his ninetieth birthday in 1991, Rodrigo was raised to the nobility by King Juan Carlos I with the title "Marqués de los jardines de Aranjuez." He was ultimately given Spain's highest international honor, the Prince of Asturias Prize for the Arts, in 1996. The government of France also recognized Rodrigo's importance, making him a Chevalier de la Légion d'honneur in 1960 and promoting him to Commandeur des Arts et des Lettres in 1998. By the end of his life, he had also received six honorary doctorates from universities worldwide. Rodrigo died in 1999; he and his wife are both buried at the cemetery at Aranjuez.