De la Renta received an international fashion education. At 18 he left the Dominican Republic to study painting at the San Fernando Royal Academy of Fine Arts in Madrid. There, he began working as an illustrator for fashion houses, a position that led eventually to the post of assisting Spain's leading designer, Cristóbal Balenciaga (Balenciaga, Cristóbal). In 1961 he settled in Paris and worked as the assistant to Lanvin-Castillo's head designer, Antonio del Castillo, before moving to New York City in 1963 to design the couture and ready-to-wear collections for Elizabeth Arden. In 1965 he established his own eponymous company in New York.

De la Renta's label quickly came to represent casual luxury to society women—many of them friends of his then-wife, Françoise de Langlade, editor of French Vogue—among whom he effortlessly circulated. He first gained attention for his gypsy- and Russian-inspired collections in the late 1960s and early '70s, which suggested the cosmopolitan sophistication that would characterize his creative output over the following decades. These collections were always distinctly modern, yet they also possessed a romantic, feminine quality, reflecting his grounding in both American sportswear and European couture. Consistent elements of his vision include a vibrant colour palette, delicate silk prints, the use of ruffles, and soft silhouettes. He is perhaps best known for his evening wear and suits for women, which over the years became wardrobe staples for his faithful clientele of socialites and for former First Ladies Jacqueline Kennedy Onassis (Onassis, Jacqueline Kennedy), Nancy Reagan (Reagan, Nancy), and Hillary Clinton (Clinton, Hillary Rodham). His label also produced menswear, accessories, perfume, and fine china.

Although he settled in New York, de la Renta also marketed his work in Latin America, where it became very popular, and remained active in his native Dominican Republic, where his charitable activities and personal achievements earned him the Juan Pablo Duarte Order of Merit and the Order of Cristóbal Colón. Active in the American fashion community, he served as president of the Council of Fashion Designers of America (CFDA) from 1973 to 1976 and 1986 to 1988, and in 1990 the CFDA gave him its Lifetime Achievement Award. He became the first American designer to be awarded a major post at a French couture house when in 1993 he became head designer at Pierre Balmain (Balmain, Pierre). Proving the longevity of his career, he won the CFDA Womanswear Designer of the Year Award in 2000.