A member of the House of Cornaro, Luigi Cornaro was born on February 12, 1517, the eldest of the ten children of Giovanni Cornaro, Venetian senator and Procurator of San Marco, and Adriana Pisani. His younger brother Federico Cornaro also became a cardinal. He was the grand-nephew of Catherine Cornaro, Queen of Cyprus, and the nephew of Cardinals Francesco Pisani, Marco Cornaro, and Francesco Cornaro. His cousin Andrea Cornaro also became a cardinal.
As a young man, he joined the Knights Hospitaller, becoming Grand Prior of Cyprus, an office he later resigned in favor of his younger brother Federico Cornaro.
Pope Julius III made him a cardinal deacon in the consistory of November 20, 1551. He received the red hat and the deaconry of San Teodoro on December 4, 1551.
On June 25, 1554, he was elected Archbishop of Zadar and was subsequently consecrated as a bishop. He resigned the government of Zadar on July 17, 1555 in favor of his secretary, Muzio Callini.
He was a participant in the papal conclave of April 1555 that elected Pope Marcellus II, the papal conclave of May 1555 that elected Pope Paul IV, and the papal conclave of 1559 that elected Pope Pius IV.
Under Pope Pius IV, he headed the commission charged with dealing with the riots fomented by the Carafas during the pontificate of Paul IV. He was named administrator of the see of Bergamo on March 13, 1560. He resigned the administration of Bergamo in favor of his nephew Federico on January 15, 1561, at which time he became administrator of the see of Trogir. He resigned that post on April 18, 1567. On February 26, 1561, he opted for the order of cardinal priests, and on June 21, 1564 received the titular church of San Marco.
He participated in the papal conclave of 1565-66 that elected Pope Pius V.
He opted for the titular church of San Vitale on June 2, 1568. He was Camerlengo of the Holy Roman Church from May 10, 1570 until his death, having purchased the office from the pope for 70,000 scudi that the pope wanted for war against the Ottoman Empire. Cardinal Cornaro was a fervent supporter of that war, which culminated in the 1571 Battle of Lepanto.
He was a participant in the papal conclave of 1572 that elected Pope Gregory XIII.
He died in Rome on the Feast of the Ascension, May 10, 1584. He was buried in Santa Maria in Trivio.