The opera Caterina Cornaro premiered at the Teatro San Carlo of Naples on January 18, 1844. At the opening, the opera was a complete fiasco. Donizetti was unable to oversee the production of his opera due to illness, and the Neapolitan critics were harsh in their judgment of the work. They accused Donizetti of copying himself, and purposely writing bad music to get even with the management of the theater. In later productions, the opera proved to be a success, and was one of the operas to be revived during the bel canto revival of the twentieth century, to critical and popular acclaim. The libretto was written by Giacomo Sacchero, and based on a libretto for a Halévy opera called La reine de Chypre. The opera is comprised of a prologue and two acts. The prologue takes place in Venice, while the rest of the action happens on the island of Cyprus, at a later date. The story is definitely tragic, and ends with the deaths of Lusignano, King of Cyprus, and Gerardo, Queen Caterina's first love. Lusignano is the most fully developed character in the opera. A multi-faceted individual, he shows himself to be noble and true in love and in death both to Caterina and his people. Caterina's fate is one of the more interesting of all of Donizetti's heroines. Many of his women have exceedingly tragic ends, but Caterina lives at the end of the opera, and becomes the sole ruler of Cyprus.

The score contains much beautiful music and some of Donizetti's most adventurous and expressive harmonic writing. The scenes of violence are extremely musically interesting, and give the opera its dark character. The chorus "Sangue ci Vuole!" or "We want blood," literally, which is sung during a mob revolt, is filled with dissonance and strong, vigorous writing. Other highlights include a friendship duet between Gerardo and Lusignano. Friendship duets, in which two male protagonists formerly at odds vow to live as brothers, was a favorite ensemble type of Italian audiences. The romanza for Lusignano "Ah! Non turbati" helps develop his character, and the scene of insurrection at the opening of the second act leads to the opera's violent conclusion.

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