On 31 January 1825, local architect Carlo Barabino submitted his design for the opera house which was to be built on the site of the church of San Domenico.

In 1892, Genoa commemorated the 400th anniversary of Columbus' discovery of America and to celebrate the occasion the Carlo Felice was renovated and redecorated at a cost of 420,000 lire (nearly £17,000).

The hall was altered many times in the years 1859–1934, and remained remarkably unscathed by war until 9 February 1941 when, during Operation Grog, a shell fired by a British warship hit the roof, leaving a large hole open to the sky and destroying the ceiling of the auditorium which had been a unique example of 19th-century rococo extravagance, its main feature being a wide circle of angels, cherubs and other winged creatures in brightly painted high relief.

On 5 August 1943 incendiary bombs started a backstage fire which destroyed all scenery and wooden fittings, but did not reach the main auditorium.

Finally, an air raid in September 1944 caused the destruction of the front of the theatre leaving virtually only the outside walls and the corridors behind the tiers of boxes standing.