Along with Domenichino and Francesco Albani, Reni began his training in the workshop of Denys Calvaert. At the age of 20, he joined the Carracci Academy and soon traveled to Rome as an independent master. He skillfully assimilated the characteristics of Raphael, the Carracci, and other leading artists into his own individual style. After returning to his hometown in 1614, he ran a large and prosperous studio that produced works for clients all over Europe. In his day he was regarded as the best painter in Italy and later became known as the "divine Guido."

For Reni and his contemporaries, the Four Evangelists were a popular subject that appealed to the taste and uses of both church and private patrons. This set is significant for two reasons: it is the only known complete set, and it joins the Vatican version of St. Matthew in being considered autograph. A number of variants and copies are known, but this set is probably Reni's original treatment of the series.

Reni shows all four gospel writers in the midst of writing the inspired account of Christ's life. Each man is identified by the traditional symbolism ascribed to him in light of the four beasts found in Ezekiel chapter one and Revelation chapter four. Matthew is shown carefully transcribing words relayed by an angel. Mark is intently writing in a book supported by the head of a lion, while Luke looks heavenward as a shadowy ox looms over his shoulder. Finally, John is penning his account under the watchful eye of an eagle.