During the Nixon administration, Leonore Annenberg served at the side of her husband, publisher and philanthropist Walter H. Annenberg at the Court of St. James's.  While in their post  in Great Britain, Mrs. Annenberg oversaw the renovation of the U.S. ambassador's residence, Winfield House, a project the Annenbergs funded. While in London, Mrs. Annenberg also founded the American Friends of Covent Garden. Mrs. Annenberg was chairman emeritus of the Foundation of Art and Preservation in Embassies, a private non-profit, non-partisan foundation established to assist the United States Department of State in procuring and maintaining fine and decorative art, including furniture and paintings for United States Embassies, Chanceries, and Ambassadorial residences. In addition, Mrs. Annenberg was a member of The Committee for the Preservation of The White House.

In 1981 Lee Annenberg became Ronald Reagan's first Chief of Protocol.  Mrs. Annenberg and three former U.S. presidents, Presidents Nixon, Ford and Carter represented the U.S. government at the funeral of Egyptian president Anwar Sadat in 1981.

During their more than 50 year marriage, Lee and Walter Annenberg assembled one of the world's finest collections of Impressionist and Post Impressionist paintings which they displayed at their homes outside Philadelphia, in Rancho Mirage California and, during their time in Great Britain, at Winfield House. At Ambassador Annenberg's death the paintings were given to the Metropolitan Museum of Art in New York City where they hang in a permanent exhibit

When Walter Annenberg died in 2002, Lee Annenberg assumed the reins of the Annenberg Foundation and the Annenberg Foundation Trust at Sunnylands. As a philanthropist, she focused on increasing educational opportunity and safeguarding the national's cultural institutions. From the time of the Annenberg Foundation's founding in 1989 to her death in 2009, she and Walter Annenberg designated more than 3 billion dollars worth of grants and gifts to groups that included major research universities, hospitals, medical centers, and cultural and civic organizations. A list of their grants can be found on the Annenberg Foundation website. Under her leadership, the Annenberg Foundation Trust at Sunnylands developed the award winning programming on the Constitution and adolescent mental health found elsewhere on this site.

Mrs. Annenberg was a trustee emerita and a member of the Acquisitions Committee of the Metropolitan Museum of Art, member of the Board of Trustees of the Philadelphia Museum of Art, former member of the Trustee's Council of The National Gallery of Art, one of the managing directors of The Metropolitan Opera, and an honorary president of the American Friends of the British Museum. She was a member of The Distinguished Daughters of Pennsylvania and an active trustee emeritus of the University of Pennsylvania and a member of the Visiting Committee to the Department of European Paintings.  Mrs. Annenberg was the past president and an honorary trustee of the Palm Springs Desert Museum, and an honorary trustee of The Performing Arts Council of the Los Angeles Music Center. She was a former member of the boards of the Pennsylvania Academy of the Fine Arts and the Philadelphia Orchestra Association and served as a member of the Academy of Music Committee.

She was a charter member of the Board of Overseers of the Annenberg Institute for School Reform at Brown University, and a founding member of the governing boards of the Annenberg Schools for Communication at the University of Pennsylvania and the University of Southern California. Her  husband, Walter H. Annenberg, former Ambassador to the Court of St. James's, founded these schools.

Mrs. Annenberg graduated from Stanford University with a Bachelor of Arts degree. She received the Cavaliere Dell'Ordine "Al Merito Della Republica Italiana" (1961); the Grand Officio Order of Orange-Nassau from the Netherlands (1981); the Wagner Medal for Public Service from the Robert F. Wagner Graduate School of Public Service at New York University, the Colonial Williamsburg Churchill Bell Award (1993), the National Medal of Arts from the National Endowment of the Arts (1992) and the University of Pennsylvania Medal for Distinguished Achievement (1994), the Crystal Award from the Union League of Philadelphia, Pennsylvania (2001), the Andrew Carnegie Medal of Philanthropy (2001), the Pat Nixon Ambassador of Goodwill Award (2002), the Collaborative Partnership Award from Foundations, Inc. (2002), and an Honorary Fellow of Eton College - Windsor (2003). Mrs. Annenberg was awarded honorary doctorate degrees from Pine Manor College (1982); LaSalle University (1987); The University of Pennsylvania; Brown University; The University of Southern California (1998) and Brandeis University (1999). Lee Annenberg was also a member of both the American Academy of Arts and Sciences and the American Philosophical Society and an honorary fellow of the Royal Academy of Arts.