Her husband’s election as the 41st President elevated the plain-spoken, faux-pearl wearing, distant relative of President Franklin Pierce to First Lady from January 20, 1989 to January 20, 1993. Aware that she was not elected and carried no official duties, Mrs. Bush instructed her staff: “Each day we should do something to help others.” So along with the endless entertaining and public ceremonies, she went to soup kitchens, homeless shelters and senior centers. She participated in events supporting worthy causes from veterans’ hospitals, to teen pregnancy programs, to the Salvation Army and the Boys & Girls Clubs.

Notably at the time, Mrs. Bush visited facilities for AIDS patients, held infected babies and hugged adults. In so doing, she helped erase the stigma of that disease, and encouraged her husband’s administration to increase funding for AIDS research and treatment.

Her commencement address to Wellesley College's graduating class in June of 1990 -- which was initially opposed by a faction of the student body, but defused when Mrs. Bush invited the visiting Raisa Gorbachev to accompany her -- was later ranked #45 by American Rhetoric in their list of the 20th Century's greatest speeches.

As First Lady, Mrs. Bush took her promotion of the family literacy movement to a new level of national and even global awareness when she launched the Barbara Bush Foundation for Family Literacy, focusing simultaneously on early childhood education for preschoolers and adult literacy. In 1990, she published a second book, Millie’s Book: As Dictated to Barbara Bush, which sold more than 300,000 copies in its first year and raised nearly $900,000 for her new foundation. Later in 1990, she launched "Mrs. Bush's Story Time," a national radio program that stressed the importance of reading aloud to children. In 1991, Mrs. Bush and other advocates celebrated the passage of the National Literacy Act, which created the National Institute for Literacy and permitted the use of libraries and other municipal property as evening literacy centers for adults.

"The best way to explain how I felt about my 'job' as First Lady is to share with you a letter I wrote during my first year in the White House but never sent," she wrote in A Memoir. Criticized by Lady Bird Johnson's press secretary Liz Carpenter for not speaking out more on issues where she might have differed with her husband, Mrs. Bush responded in the un-sent letter: "Long ago I decided in life I had to have priorities. I put my children and my husband at the top of my list. That's a choice that I never regretted. If I had any regrets, and who doesn't, I wish I'd taken time to listen a little longer, look a little deeper, and spend even more time with our children ... After spending several months pondering over exactly what cause I would take on if George got elected to 'high' office, I realized a more literate America would benefit every single thing I worry about: crime, unemployment, pollution, teen-age pregnancy, school dropouts, women who are trapped in welfare ... Abortion, pro or con, is not a priority for me. ERA is not a priority for me, nor is gun control. I leave that for those courageous enough to run for public office ... Teaching that all people are equal is a priority for me. Feeding the hungry and housing the poor is a priority for me. Keeping kids in school is a priority for me, and I could go on and on. I do not want to defuse or confuse my top priorities."

During the 1992 campaign, a seasoned political strategist from an opposing camp observed: "In the 30-some years I've been around American politics, she's far and away the greatest political spouse I've seen."