He was educated at the liberal arts Cathedral school at Seville, learning the trivium and quadrivium. He mastered classical Latin and learned some Hebrew and Greek. Records are scarce about his early life and whether he ever joined a monastery, but in 619 he declared anathema harassing a monastery or monks. When his brother Leander, bishop of Seville, died in 600 or 601, Isidore was named his successor. He set about to eradicate any remaining traces of Arianism among the Visigoths, and was largely successful. He presided over a couple synods and a Council of Toledo.
His influence on the following centuries came more from his writings than his efforts against heresy. One was the De fide catholica contra Iudaeos, ("On the Catholic Faith against the Jews"). Like Augustine of Hippo, Isidore recognized the importance of the Jews because of their role in the Second Coming of Christ. In the Fourth Council of Toledo, however, he advocated removing children from the parents of "Crypto-Jews": Jews who were hiding their Judaism by acting as Christians. His argument was that the parents had probably had the children baptized as part of their subterfuge, and so educating the children as proper Christians was appropriate. (The Summa Theologica of Aquinas in the 13th century would state "it was never the custom of the Church to baptize the children of Jews against the will of their parents.")
He also wrote Historia de regibus Gothorum, Vandalorum et Suevorum ("History of the Kings of the Goths, Vandals and Suevi"), covering from 265 to 624.
He was the earliest Christian writer to try to summarize the knowledge of the world. His encyclopedic work, the Etymologiae, compiled his own thoughts with pieces from numerous Roman handbooks and miscellanies. It was so extensive (20 volumes with 448 chapters total)—one bishop described it as "practically everything that it is necessary to know"—that some of the works he drew from were no longer thought to be necessary to be copied and preserved.