Girardon attracted the attention of Chancellor Pierre Séguier (Séguier, Pierre), who brought him to Paris to study under François Anguier (Anguier, François) and afterward sent him to Rome. Girardon returned to France about 1650, becoming a member of the Royal Academy of Painting and Sculpture in 1657. He worked for Nicolas Fouquet (Fouquet, Nicolas) at Vaux-le-Vicomte and, after the minister's fall, was extensively employed in the decoration of the royal palaces. In 1663 he was working under Charles Le Brun (Le Brun, Charles) on the Galerie d'Apollon at the Louvre and in 1666 received the commission for his most famous work, the Apollo Tended by the Nymphs, for the Grotto of Thetis at Versailles. The inspiration for this pictorial sculptural work (later moved and its grouping altered) seems to derive partly from Hellenistic sculpture (particularly the Apollo Belvedere) and partly from Nicolas Poussin (Poussin, Nicolas)'s paintings. Of his other works for Versailles, the most notable are the relief of the Bath of the Nymphs (1668–70), perhaps inspired by Jean Goujon (Goujon, Jean)'s Fontaine des Innocents, and The Rape of Persephone (1677–79; pedestal completed 1699), in which he challenges comparison with Giambologna's Rape of the Sabines. The effect of this group is marred by its present situation in the centre of the colonnade at Versailles, where it can be seen from all sides instead of from a fixed viewpoint as originally intended.

Although superficially a Baroque artist, Girardon's deep-seated classical tendencies also emerge in the serene solemnity of his two principal works outside Versailles: the equestrian statue of Louis XIV in the Place Vendôme (1683–92), which was destroyed in 1792 during the French Revolution, and his gisant for the tomb of Richelieu in the church of the Sorbonne (begun 1675). Although influenced by the works of Gian Lorenzo Bernini (Bernini, Gian Lorenzo) and the Roman Baroque school, Girardon's works are less vigorous and more restrained than most Baroque sculpture.

The classical bent of his mind and his abilities as a decorator made him the ideal collaborator with Le Brun, just as Antoine Coysevox (Coysevox, Antoine) was with Le Brun's successor, Jules Hardouin Mansart (Mansart, Jules Hardouin-). As Coysevox's star rose, that of Girardon sank, and he received few royal commissions after 1700.