Her career, which saw her move from writing unproduced plays to helping create some of the earliest television dramas to becoming a kind of professional New Yorker, goes far beyond the charm of that one book. She called her 1962 memoir Underfoot in Show Business, and it chronicled the struggle of an ambitious young playwright to make it in the world of New York theatre in the 1940s and 1950s. She worked in publicists' offices and spent summers on the "straw hat" circuit along the East Coast of the United States, writing plays that were admired by some of Broadway's leading producers but which somehow never saw the light of day.

She wrote and edited scripts for a variety of early television dramas produced out of New York, all the while continuing to try to move from being what she called "one of the 999 out of 1,000 who didn't become Moss Hart." [later editions on the book changed this reference to Noel Coward, perhaps supposing later readers might not be familiar with Moss Hart. But when "Underfoot" was originally published, it was only a few years after Hart's memoir "Act One" had been a best seller.] When the bulk of television production moved to California, her work slowly dried up, and she turned to writing for magazines and, eventually, to the books that made her reputation.

First published in 1970, the epistolary work 84 Charing Cross Road chronicles her 20 years of correspondence with Frank Doel, the chief buyer for Marks & Co, a London bookshop, on which she depended for the obscure classics and British literature titles around which her passion for self-education revolved. She became intimately involved in the lives of the shop's staff, sending them food parcels during England's post-war shortages and sharing with them details of her life in Manhattan.

Due to financial difficulties and an aversion to travel, she put off visiting her English friends until too late; Doel died in December 1968 from peritonitis from a burst appendix, and the bookshop eventually closed. Hanff did finally visit Charing Cross Road and the empty but still standing shop in the summer of 1971, a trip recorded in her 1973 book The Duchess of Bloomsbury Street. In "Duchess", Hanff describes her visits with friends and fans to various locations and places of literary and historical interest in London and Southern England. This trip was a highlight of her life - her modesty and sense of humor are evident as she talks about the friends, including Frank Doel's wife, Nora, and daughter, Sheila, who were so devoted to her because of 84 Charing Cross Road, and her love of London.

In the 1987 film adaptation of Charing Cross Road, Hanff was played by Anne Bancroft, while Anthony Hopkins took the part of Frank Doel. Anne Jackson had earlier played Hanff and Frank Finlay Doel in a 1975 adaptation of the book for British television. Ellen Burstyn recreated the role on Broadway in 1982 at the Nederlander Theater in New York City. Elaine Stritch also played Helene Hanff in a television adaptation of 84 Charing Cross Road.

Hanff never married. In the 1987 movie, a photo of a US serviceman is shown in her apartment during the period of World War II, a portrait at which she smiles fondly, suggesting to the viewer that Hanff never married, due to this naval officer's death. No such person is mentioned in her autobiographical Underfoot and none of her writings suggests that she ever had any lasting, or even short-term, romantic relationship with any person. In Duchess she confides to her diary that she was irritated by 'a lot of togetherness' with one of her male English fans who had taken her to Stratford-upon-Avon and Oxford on a two-day driving trip. This implies that Hanff preferred her own company and had no need of a life partner. Her relationship with Frank Doel, warm as it was, was entirely literary.

One interesting facet of Hanff's career is that she was asked by editor Genevieve (Gene) Young of Harper & Row to write her autobiography as a failed playwright-cum-successful television writer before she became notable as an author, publication of Underfoot In Showbusiness preceding 84 Charing Cross Road by eight years.

Hanff later put her obsession with British scholar Sir Arthur Quiller-Couch to use in a book called Q's Legacy (1985). Other books include Apple of My Eye (1977 and updated in 1988), an idiosyncratic guide to New York City, and Letter from New York (1992), which reprinted the five-minute talks she gave each month on the BBC's Woman's Hour radio broadcasts between 1978 and 1984.

Hanff was never shy about her fondness for cigarettes and martinis, but nevertheless lived to be 80, dying of diabetes in 1997 in New York City. The apartment building where she lived at 305 E. 72nd Street has been named "Charing Cross House" in her honor. A bronze plaque next to the front door commemorates her residence and authorship of the book. In England, a bronze plaque commemorates the bookstore featured in 84, Charing Cross Road, although the building now houses a restaurant.