In the picturesque town of Montefalco, Umbria, Benozzo received the first prestigious commissions that allowed him to demonstrate his talent on his own. It is highly probable that Pope Nicholas V, protector of that town’s Reformed Franciscans of St. Fortunatus, having already had the opportunity to admire the painter’s work, interceded in his favour.

In 1450, Benozzo painted the fresco (now in a fragmentary state) of the Madonna and Child enthroned with angel musicians for the renovated Franciscan convent of St. Fortunatus. In that same church, he painted a Saint Fortunatus enthroned surrounded by angels, also now in a poor state of repair, and a Virgin and Child with Saints Francis and Bernard, on the lunette of the entrance doorway, using the same technique.

Benozzo was then engaged to paint the beautiful altarpiece that decorated the main altar. This panel painting, depicting the Madonna of the Girdle, is currently housed in the Vatican Picture Gallery having been donated to Pope Pius IX in 1848 by the town of Montefalco. In the upper section of the altarpiece, on a gold background and with some of its original frame still intact, the Madonna is pictured surrounded by angels and handing her girdle to Saint Thomas as proof of her ascension to Heaven. Gozzoli once again succeeded in expressing his great decorative talent in the scenes from the life of the Virgin illustrated in the predella. He later illustrated the subject of the miracle of the girdle with greater wisdom and maturity in the Tabernacle of the Madonna of the Cough - one of his last works - which he painted in Castelfiorentino.

He was then engaged by Jacopo di Mattiolo to paint the main chapel of the church dedicated to Saint Francis which the conventual monks had built within the town of Montefalco. The frescoes of the Stories of the Saint were probably painted in a very short space of time. Indeed, Benozzo used an approved team of co-workers for the painting of this cycle and the numerous others he painted in the town, including those in the chapel dedicated to Saint Jerome in the same church. The learned client of the Franciscan cycle was also portrayed in the charming panel painting, now housed in the Kunsthistoriches Museum in Vienna, depicting the Madonna and Child, two curtain-bearing angels, Saints Francis and Bernard and the donor.

During his stay in Montefalco, Benozzo was also commissioned to work on an ancient image of Saint Claire frescoed in the Augustinian convent. Some of the last works he produced during this period were the luminous panel painting of Saint Ursula, two curtain-bearing angels and the donor, now owned by the National Gallery of Art in Washington.