Helleu studied at the École des Beaux-Arts in 1876 in the atelier of Jean-Léon Gerome. In Paris, his circle of intimate friends included fellow artists Giovanni Boldini, Alfred Stevens, Edgar Degas, Rodin, Claude Monet and notably the Americans Whistler and Sargent, with whom he briefly shared a studio.

Helleu exhibited several large pastel portraits to great acclaim at the Salons of 1885 and 1886, including one of Alice Louis-Guérin, to whom he became engaged in 1885. He and Alice married in 1886 at the church of Saint-Pierre in Neuilly. Although friendly with many of the Impressionist painters and invited by Degas to participate in the eighth and final Impressionist exhibition of 1886, Helleu declined to do so. He exhibited six pastels at the Salon des Pastellistes at the Galerie Georges Petit in 1887, including two further portraits of Alice. At this time he first met Comte Robert de Montesquieu, who was to become his leading patron and who, in 1913, published the first important monograph on the artist.

In 1889 Paul and Alice Helleu spent some time with Sargent at Fladbury in England, and he made several studies of Alice and an oil of Paul painting her (Brooklyn Museum, New York). The 1890s were a successful decade for Helleu, who moved comfortably in society in both France and England. He obtained numerous lucrative portrait commissions and enjoyed considerable financial success. Helleu also met and enjoyed a long friendship with Marcel Proust, who is thought to have based the character of the painter Elstir in A la Recherche du Temps Perdu on him.

Encouraged by Sargent, Helleu began travelling to America in 1902, where his reputation had preceded him, and he enjoyed further success drawing elegant Society women. His subjects included the Comtesse Greffulhe, Queen Alexandra and Consuelo Vanderbilt, the Duchess of Marlborough. These works were greatly admired by his contemporaries. His preferred subject remained Alice, whom he drew many times.

The writer Edmond de Goncourt wrote of Alice Helleu that [s]he was incapable of making a movement that was not graceful and elegant, and ten times a day he [Paul-César Helleu] tried to capture those movements with a quick drypoint sketch.

In 1931, four years after Helleu’s death, a retrospective exhibition of his work was held at the Galerie Charpentier in Paris. Today his work can be found in many museum collections, including the Museum of Fine Arts, Boston, the Musée du Luxembourg, Paris and the Musée d'Orsay, Paris.