A friend in Austin introduced Lady Bird to Lyndon Baines Johnson, then a 26-year-old Congressional aide, who proposed after their first date. She did not want to rush into marriage, but thanks to his persistence she accepted his proposal ten weeks later. It was Lady Bird's inheritance that funded the launch of her husband's campaign to become a Congressman; when he enlisted in the navy at the start of the Second World War, Lady Bird ran his congressional office. During the war, Lady Bird spent $17,500 of her inheritance to buy a small local radio station in Austin and later expanded to buying a television station in 1952 (in spite of her husband's objections). Lady Bird managed both of those enterprises and in doing so she became a self-made millionaire.

As Second Lady of the United States of America, she acted as a substitute for the First Lady, Jaqueline Kennedy, at a number of events which she would later say prepared her well for her time as First Lady. That time arrived sooner than Lady Bird could ever have expected - after the assassination of John F. Kennedy in 1963 she found herself looking on as her husband was sworn in as President on Air Force One. During her time in the office of First Lady, Lady Bird employed her own press secretary and chief of staff (being the first First Lady to do so). In 1964, she defied death threats during a 1,682-mile tour of the Deep South aboard a chartered train, the Lady Bird Special, to speak directly to those who opposed her husband's recent passage of the Civil Rights Act. In doing so, she became the first President's spouse to campaign independently of her husband; as a native Texan, she later said she had thought it important that someone speak to Southern voters with respect while trying to change as many minds as possible about the necessity of desegregation and the importance of ending racial discrimination.

After the death of her husband in 1973, Lady Bird continued working on a number of personal projects and managing her investments. She spoke out for women's rights at the 1977 National Women's Conference alongside notable activists Betty Friedan and Gloria Steinem, and her environmental activism continued into her later years. Lady Bird died in 2007 at the age of 94 and was buried next to her husband at the Johnson family cemetery in Stonewall, Texas.

Lady Bird was also the driving force behind the 1965 Highway Beautification Act, a piece of legislation that aimed to replace highway billboards and junkyards with trees and wildflowers - so much so that the legislation was nicknamed "Lady Bird's Bill". As the first First Lady to lobby congress for the passage of a bill, she gained a reputation as a trailblazer who strongly believed that clean streets and a beautiful environment would make the US a better place to live. The Act brought nature back into the daily lives of millions of citizens, and Lady Bird's campaigning brought the subject of conservation to the public sphere.

Even after her time in the office of First Lady came to a close, Lady Bird continued to campaign for several beautification projects, including Town Lake in Austin (which would later be renamed in her honour), and served on the advisory board of the National Park Service. Together with actress Helen Hayes, she founded the National Wildflower Research Center near Austin, Texas, in 1982 which would later be renamed the Lady Bird Johnson Wildflower Center. Today, the wildflower centre is still dedicated to the preservation and use of native plants through research and education. It is often seen as an embodiment of Lady Bird's vision to protect and preserve the natural beauty of the US, both taking care of nature and communities while integrating the two. After founding the centre, Lady Bird would go on to write: "I'm optimistic that the world of native plants will not only survive, but will thrive for environmental and economic reasons, and for reasons of the heart."