Barbara Bush was diagnosed with Graves' disease in 1988. Later on, she suffered from congestive heart failure and chronic obstructive pulmonary disease ‎(COPD)‎. Bush was a heavy smoker for 25 years, quitting in 1968 when a nurse condemned her smoking in her hospital room after surgery.

In November 2008, Bush was hospitalized for abdominal pains and underwent small intestine surgery. She underwent aortic valve replacement surgery in March 2009.

Bush was hospitalized with pneumonia on New Year's Eve 2013 and was released from the hospital a few days later.

On April 15, 2018, her family released a statement regarding her failing health stating that she had chosen to be at home with family, desiring "comfort care" rather than further medical treatment. According to family spokesman Jim McGrath, her decision came as a result of "a series of recent hospitalizations".