Guglielmo de Sanctis studied at the Accademia di San Luca in Rome from 1842 and took additional lessons in the studio of the painter Tommaso Minardi. From 1851, de Sanctis worked in the studio of Cesare Marianecci in Florence. He continued to paint in the style of his Roman teacher Minardi and frescoed his funerary monument on the Campo Verano in Florence. De Sanctis executed religious subjects, history paintings and above all portraits of prominent personalities, for example King Umberto I of Italy and Gioacchino Rossini. On behalf of the Italian government, he selected the painters who were allowed to participate in the Universal Exhibitions of 1871, 1872, 1876 and 1885. In 1893, he became an honorary member of the Accademia di San Luca. In 1905, de Sanctis donated his art collection to the city of Rome, including paintings by himself and contemporaries.