In this chapel, this jewel of rare beauty, art and faith find a perfect union. The icon of the Salus Populi Romani, recounted by pious tradition to have been painted by St. Luke the Evangelist, welcomes all who come before her with her maternal gaze. In 1605, Pope Paul V Borghese (1605-1621) was elected to the pontificate and it is to him that we owe this chapel, known as either the Borghese or Pauline chapel. The structure is symmetrical in design and architectural plan with the Sistine chapel on the opposite side of the Basilica. Like the Sistine, it is shaped as a Greek cross and articulated in the Corinthian order. Powerful pilasters support four large arches, upon which rests the dome.

Built by order of Paul V to house the image of the Madonna Salus Populi Romani, the chapel was designed by Flaminio Ponzio (1560-1618) between the years 1606 and 1612. The consecration of the site took place on January 27, 1613 but the decorative work continued into the next year. The chapel cost the Apostolic Chamber 299,261 scudi and 61 baiocchi. Executed twenty-five years after the Sistine chapel, the decoration of the Borghese chapel seems more impetuous and freer in style. From its precious marbles highlighted by gilded cornices, bronze angels radiant with light and stucco angels in lively and joyous poses, to the majestic altar, made of an intense blue stone, the refined, grandiose monuments of the Borghese chapel are indicative of the first signs of Baroque taste and spirit.

The first model for the altar was made of pear wood in 1607, and the following year the artisan Pompeo Targoni began the work on the present altar which was completed in 1612. The work glitters with gilt metals, cast in the form of airy and lively angels who support the frame, created by Camillo Mariani, which encloses the Salus Populi Romani. Its wealth of detail and strong contrasts in light and shadow are derived from the Florentine Mannerist movement led by Jacopo Sansovino and seem to lighten the heavy mass of architecture with its lyrical, expressive accents. Mariano also sculpted the figure of St. John the Baptist. Without a doubt the most interesting piece of decorative sculpture on the grand altar is the low relief on the front. This work of Stefano Maderno shows Pope Liberius tracing the perimeter of the basilica in the snow. Maderno is also responsible for the angels holding scrolls as they flank the tombs. The altar table was donated in 1749 by Princess Agnese Colonna Borghese, who is commemorated by her coat-of-arms engraved upon it.

Giuseppe Cesari, also known as the Cavalieri d'Arpino frescoed the large lunettes above the altar. On the left, the painting represents the apparition of the Madonna and St. John the Evangelist to St. Gregory the Wonderworker; on the right it shows people bitten by the serpent of heresy before the Temple of God among a crowd of true believers. The same artist also painted the great prophets in the spandrels of the cupola. Isaiah is represented with white hair and a beard, in a blue tunic covered by a red robe and bare feet. Jeremiah is depicted as bald and wearing a long grey beard and blue and gold robes that fall to his feet. Ezekiel appears more youthful, beardless with blond hair and bare-armed in a red robe with blue stripes. Finally, the artist painted young Daniel, pale-skinned with long flowing hair, seated with his sleeves rolled up on his light-blue robe trimmed with gold and engulfed in a purple mantle. The Cavaliere also painted in the arch above the altar the Bishops Ignatius, Theophilus, Ireneus and Cyprian, all of whom were canonized saints.

The Assumption of Mary was painted inside the cupola by Ludovico Cardi nicknamed Il Cigoli . Above the clouds, the Blessed Virgin is transported towards the Heavens. The moon underneath her feet was painted exactly as it had been revealed through the telescope of Galileo, who was a friend of Cigoli. The Apostles, some seated while others are standing, gaze at the triumphant Mary as she holds a queen's scepter in her hand. Before the Virgin, who has crushed the serpent under her foot, the heavens open and the choirs of angels rejoice. From this multitude, a smaller group of cherubs draws closer to Mary, and clothed in the clouds they form a throne with their golden wings. Other cherubs blow horns, play trumpets and scatter flowers. Above them, we can see a myriad of angelic spirits, whose heads alone are fully visible.

The lantern of the cupola contains six little windows and in the very summit the Eternal Father is represented crowned by scores of seraphim.

Giovanni Baglione frescoed the vault of the nave with Doctors of the Church and Evangelists and in the arch above the entrance he painted emperors Julian the Apostate, Leo IV and Costantine V, all of whom persecuted the Church. In the oval above the altar, Giovanni Baglione painted the image of St. Luke.

Guido Reni frescoed the right-hand arch with images of Saints Cyril of Alexandria, Idelphonse and John Chrysostom together with Saints Pulcheria, Gertrude and Cunegonde. On the left arch, Saints Eraclius and Narsete stand beside the powerful figures of St. Francis and St. Dominic. On this same arch, above the funeral monument of Paul V, Reni painted an image that shows the Eternal Father in anger over the wickedness of men. Several of the putti arranged on the frieze running around the chapel above the capitals were executed by Stefano Maderno. French sculptor Nicholas Cordier carved the image of David, conqueror of Goliath, pointing towards his descendant, the Messiah, as well as the statues of Aaron, St. Bernard and St. Athanasius. The sculpture of St. Joseph was done by Ambrogio Buonvicino.

The papal monuments in honor of Clement VIII (1592-1605) and Paul V were both designed by Silla di Viggiu. The caryatids on the Clementine monument to the left were carved by Pietro Bernini, father of GianLorenzo.