His most important project of the first decade was decoration of the Cappella dei Santissimi Fondatori in the medieval basilica of the Abbey of Grottaferrata (1608–1610), some 20 kilometers outside Rome, where Odoardo Farnese was the titular abbot.

Appointed Papal Architect (he built little but left drawings for various projects, most notably for the façade of Sant'Andrea della Valle and for the plan of Sant'Ignazio, both in Rome), he nonetheless continued to be most active as a painter, obtaining many commissions for altarpieces in Roman churches (San Lorenzo in Miranda, 1626–27, SS.

Domenichino's work, developed principally from Raphael's and the Carracci's examples, mirrors the theoretical ideas of his friend Giovanni Battista Agucchi, with whom the painter collaborated on a Treatise on Painting.

One of the most famous incidents in the history of art that centered on concepts of Imitation arose when Lanfranco accused Domenichino of plagiarism, specifically of having stolen the design of his great Last Communion of St. Jerome from an altarpiece of the same subject in Bologna by his former teacher, Agostino Carracci.

To prove his point, Lanfranco circulated a print after Agostino's painting, prompting painters and critics to take sides, most of whom—including Poussin and the antiquarian-critic-biographer Bellori—strongly defended Domenichino's work as being praiseworthy imitation.

In addition to his interest in the theory of painting (he was well educated and bookish), Domenichino was devoted to music, not as a performer but to the invention of instruments suited to the stile moderno or to what Monteverdi dubbed the "seconda pratica."

Some 1750 drawings in the Royal Collection at Windsor Castle attest to the assiduous study underlying Domenichino's work—figural, architectural, decorative, landscape, even caricature—and to the painter's brilliance as a draftsman.

The Balance reflects Domenichino's high standing in the history of European taste— until John Ruskin in the 1840s wrote his devastating attacks on Bolognese Baroque painting in his Modern Painters.

Modern scholarship, led by Luigi Serra, John Pope-Hennessy, Evelina Borea and Richard Spear, who in 1982 published the first catalogue raisonné of all of Domenichino's paintings and preparatory drawings, has resurrected the artist from the Victorian graveyard and reestablished his place among the most important and influential painters of seventeenth-century Italy.