Barbara Weidman met Nathaniel Branden because of their mutual interest in Ayn Rand's works. They became personal friends of Rand in 1950, and when they married in 1953, Rand and her husband, Frank O'Connor, served as the matron of honor and best man. Barbara and Nathaniel Branden co-wrote Who Is Ayn Rand? in 1962. Barbara Branden's essay in the book was the first biography of Rand. When it was written, Rand considered Barbara Branden to be one of the most important proponents of Objectivism.

She served as the Executive Director of the Nathaniel Branden Institute, and gave a series of lectures on "Principles of Efficient Thinking."

In 1954, Nathaniel Branden began a romantic affair with Rand, a relationship which continued into the mid-1960s, according to Ms. Branden's later biography of Rand. Despite Barbara Branden's knowledge and nominal acceptance of the affair at the time, she now believes that it contributed to her eventual separation from Nathaniel Branden in 1965, although he had begun an affair with a third woman by that point.

In 1968, when Rand terminated her association with Nathaniel Branden after she discovered that he had become involved with actress Patrecia Scott more than four years earlier, she likewise disassociated herself from Barbara Branden for keeping this fact from her. The details of these events remain controversial.

In 1986, Barbara Branden published another biography of Rand, The Passion of Ayn Rand. The book was made into an Emmy-award winning motion picture in 1999 starring Helen Mirren as Rand and Eric Stoltz as Branden.