The Grande Salle du Palais-Royal (or Théâtre du Palais-Royal) on the rue Saint-Honoré in Paris was a theatre in the east wing of the Palais-Royal, which opened with a performance of Jean Desmarets' tragicomedy Mirame. The theatre was used by the troupe of Molière from 1660 to 1673 and as an opera house by the Académie Royale de Musique from 1673 to 1763, when it was destroyed by fire. It was rebuilt and reopened in 1770, but again was destroyed by fire in 1781 and not rebuilt.

The Palais-Royal was originally known as the Palais-Cardinal, since it was built in the 1630s as the principal residence of Cardinal Richelieu. The palace already had a small theatre, the Petite Salle des Comédies, located in the wing running north from the east end of the corps-de-logis. On a 1673 plan it is marked "Petite Salle des Ballets". In 1637 Richelieu asked his architect Jacques Le Mercier to begin work on a larger theatre, located east of the entrance courtyard to the south. The new theatre was built between 1639 and 1640 "at the staggering cost of 300,000 livres—of which 100,000 livres was allocated to stage machinery."

The hall, initially known as the Grande Salle du Palais-Cardinal (Large Hall of the Palais-Cardinal), was one of the earliest theatres in France to use the proscenium arch, seen earlier in Italian theatres, with a solid stage curtain, raised and lowered by a roller behind the arch. It had two balconies, a capacity of about 3,000 spectators and a stage equipped with the latest in theatre machinery.

Upon Richelieu's death on 4 December 1642, he left the property to Louis XIII, and it became known as the Palais-Royal, although the name Palais-Cardinal sometimes still continued to be used. Louis XIII died a few months later, on 14 May 1643, and despite his will, his widow, Queen Anne of Austria, at the request of her son, the four-year-old King Louis XIV, became regent without restrictions on 18 May. Anne, the king and his younger brother Philippe moved from the Louvre to the Palais-Royal in October, and her first minister, Cardinal Mazarin, moved there a few months later. Anne was fond of Italian theatre and music, and Mazarin arranged for Italian actors and singers to come to Paris to perform. The establishment of a resident Italian opera became state policy, and the Palais-Royal became the venue for a number of Italian productions. Egisto (probably a version of Egisto with music by Francesco Cavalli) was given at the Palais-Royal on 13 February 1646. Luigi Rossi's new opera Orfeo premiered in the theatre on 2 March 1647. Giacomo Torelli designed the sets and theatre machinery and remodeled the theatre for the production.

The troupe of Molière and the Comédie-Italienne put on the shows here between 1660 and 1673. Molière's most notable plays were performed here, including L'École des femmes (first performed 26 December 1662), Tartuffe (12 May 1664), Dom Juan (15 February 1665), Le Misanthrope (4 June 1666), L'Avare (9 September 1668), Le Bourgeois gentilhomme (23 November 1670), and Le malade imaginaire (10 February 1673).

On the death of his old collaborator, Lully ejected Molière's troupe to a new home at the Hôtel de Guénégaud and re-used the theatre as the opera house of the Académie royale de Musique (the name of the Paris Opera at the time). Lully had much building work done on it in order to allow the installation of new stage machinery designed by Carlo Vigarani, capable of supporting the imposing sets of the operas he would later put on here. This replaced the old machinery designed by Giacomo Torelli in 1645. After Vigarani's modifications the theatre had a total capacity of about 1,270 spectators: a parterre for 600 standing, amphitheatre seating for 120, and boxes with balconies accommodating another 550. The stage was 9.4 meters across and 17 meters deep, with space in front for the orchestra 7.6 meters across and 3 meters deep.

Several of Lully's operas (tragédies en musique) were premiered at the Palais-Royal, including Alceste (19 January 1674), Amadis (18 January 1684), and Armide (15 February 1686), as well as Charpentier's Médée (4 December 1693)  In the 18th century many of Rameau's works were first performed here, including Hippolyte et Aricie (1 October 1733), Les Indes galantes (23 August 1735), Castor et Pollux (24 October 1737), Dardanus (19 November 1739), and Zoroastre (5 December 1749).

The first theatre was destroyed by the fire on 6th April 1763.

The City of Paris, which was responsible for the opera house, decided to build a new theatre on a site slightly further to the east (where the rue de Valois is located today). In the meantime the company performed in the Salle des Machines in the Tuileries Palace, which was first reduced to a size more suitable for opera by the architect Jacques-Germain Soufflot. The new theatre in the Palais-Royal was designed by architect Pierre-Louis Moreau Desproux and was the first purpose-built opera house in Paris. It had a capacity of more than 2,000 spectators.

The new theatre opened on 20 January 1770 with a performance of Rameau's Zoroastre. It is especially noteworthy as the theatre where most of the French operas of  Gluck were first performed, including Iphigénie en Aulide (19 April 1774), Orphée et Eurydice (the French version of Orfeo ed Euridice) (2 August 1774), the revised version of Alceste (23 April 1776), Armide (23 September 1777), Iphigénie en Tauride (18 May 1779), and Echo et Narcisse (24 September 1779). Among the many other works premiered here are Piccinni's Atys (22 February 1780), Grétry's Andromaque (6 June 1780), Philidor's Persée (27 October 1780), and Piccinni's Iphigénie en Tauride (23 January 1781).

The theatre continued to be used by the Opera until 8 June 1781, when it too was destroyed by fire. The Théâtre de la Porte Saint-Martin, much further to the north on the Boulevard Saint-Martin, was hurriedly built in two months to replace it. In the meantime the opera company performed in the Salle des Menus-Plaisirs on the rue Bergère.