Born in Richmond, Virginia, Blaine first studied at the Richmond School of Art (now part of the Virginia Commonwealth University). In 1942, she moved to New York City where she studied with Hans Hofmann and Stanley William Hayter. Blaine moved from strongly realistic and representational painting to abstraction due to the influence of artists such as Hofmann, Mondrian, Leger and Helion. Her loft became a gathering place for artists, jazz musician and poets. She was a member of the American Abstract Artists and one of the founding members of the Jane Street Gallery in Manhattan where she had her first show in 1945. She was championed by Clement Greenberg, who recommended her for inclusion in the 1945 Guggenheim exhibition, The Women. After a trip to Paris with Larry Rivers in 1950, Blaine became interested in 19th century European painting, especially the works of Bonnard and Vuillard. She began think about painting in terms of ‘abstract structure' and describes her experience "like opening a window. Suddenly a lot of sunlight came in." After her return from Paris, Blaine's art turned to "greater involvement with subject matter and the perceived world." Her work retained the structure and energy of her abstract paintings while depicting landscapes and still lifes. She exhibited in Ten Americans, the 1955 inaugural show at the Poindexter Gallery, and had her first solo exhibition there the following spring.
In 1959, her painting halted after contracting bulbarspinal polio from months of traveling in Egypt and Greece. Weakened by polio, Blaine was almost completely paralyzed for months and underwent intensive physical therapy. She re-taught herself how to paint despite predictions that she would never being able to paint again. Support from her many art world friends, and her own strong will, kept her spirits high. The most overwhelming support came from Eleanor Poindexter. Thomas Hess of Art News, and Leslie Katz of Arts magazine assembled an exhibition To Nell Blaine at the Poindexter Gallery, where 79 artists contributed works, and Nell was able to live on the proceeds and meet her medical expenses. While Blaine was undergoing treatment for polio, she met Dilys Evans, a nurse at New York's Mount Sinai Hospital in 1959, who later became her partner and a significant painter and illustrator. Evans was going to art school at night when Blaine offered her the job as assistant during rehabilitation, as well as a companion during travel. Blaine became her mentor and taught her painting. For six years they visited museums and galleries, traveling from New York to London, Paris, Lisbon and Madrid. Evans then studied painting and drawing in New York at the Art Students League, the New School, the Riverside Museum and won a fellowship to Yaddo in Saratoga Springs.
Polio left Blaine weaker in her right hand. She began to paint in oil using her left hand while simultaneously using her right hand for watercolor and drawing, significantly altering her control of the paint. The result was paintings that opened up more and were less rigid. The Poindexter later revealed the depth of their support for Blaine in 1964 when, amidst continued health concerns, they retrofitted a guest house for Blaine to accommodate her wheelchair on their coconut plantation on the Caribbean island of Saint Lucia. Blaine and Evans spent nearly a year there. Upon their return to New York in 1965, the Poindexter Gallery launched the exhibition, Nell Blaine: An Exhibition of Recent Paintings, 1964-1965, Oils, Watercolors & Drawings Done in St. Lucia, England and Yaddo.
After that, her paintings mostly consisted of views of the Hudson River as seen from her apartment window in New York and scenes from her garden in Gloucester, Massachusetts where she bought a house in 1975. From 1964 to 1984, Blaine continued to paint and travel for months at a time. Through her success her she kept close ties with Ellie Poindexter and many of her other friends until her death in 1996.