Federigo attained an eminence far beyond his very limited merits as a painter, and was perhaps the most popular artist of his generation. Probably no other painter has ever produced so many enormous frescoes crowded with figures on the most colossal scale, all executed under the unfortunate delusion that grandeur of effect could be attained merely by great size combined with extravagance of attitude and exaggeration of every kind. Federigo's first work of this sort was the completion of the painting of the dome of Florence's cathedral; the work had been begun by the art-historian Vasari, who wrote in the most generous language about his more successful rival. Regardless of the injury to the apparent scale of the interior of the church, Federigo painted about 300 figures, each nearly 50 feet (15 meters) high, sprawling with violent contortions all over the surface.
Federigo was recalled to Rome by Pope Gregory XIII to continue in the Pauline chapel of the Vatican the scheme of decoration begun by Michelangelo during his failing years, but a quarrel between the painter and members of the papal court led to his departure from Italy. He visited Brussels, and there made a series of cartoons for the tapestry-weavers. In 1574 he passed over to England, where he received commissions to paint the portraits of Queen Elizabeth, Mary, queen of Scots, Sir Nicholas Bacon, Sir Francis Walsingham, Lord High Admiral Howard, and others. A curious full-length portrait of Elizabeth in fancy dress, now at Hampton Court, is attributed to this painter, though very doubtfully. Another picture in the same collection appears to be a replica of his painting of the "Allegory of Calumny", as suggested by Lucian's description of a celebrated work by Apelles; the satire in the original painting, directed against some of his courtier enemies, was the immediate cause of Federigo's temporary exile from Rome. His success as a painter of portraits and other works in oil was more reasonable than the admiration expressed for his colossal frescoes. A portrait of a "Man with Two Dogs", in the Pitti Palace at Florence, is a work of some real merit, as is also the "Dead Christ and Angels" in the Boghese Gallery in Rome. Federigo was soon recalled to Rome to finish his work on the vault of the Pauline chapel. In 1585 he accepted an offer by Philip II. of Spain to decorate the new Escorial at a yearly salary of 2000 crowns, and worked at the Escorial from January 1586 to the end of 1588, when he returned to Rome. He there founded in 1595, under a charter confirmed by Pope Sixtus V, the Academy of St Luke, of which he was the first president. Its organization suggested to Sir Joshua Reynolds his scheme for founding the English Royal Academy.
Like his contemporary Giorgio Vasari, Federigo aimed at being an art critic and historian, but with very different success. His chief book, L'idea de' Pittori, Scultori, ed Architetti (Turin, 1607), is a senseless mass of the most turgid bombast. Little can be said in praise of his smaller works, consisting of two volumes printed at Bologna in 1608, describing his visit to Parma and a journey through central Italy. Federigo was raised to the rank of a cavaliere not long before his death, which took place at Ancona in 1609.