While she worked to ensure the success and legacy of her husband's presidency, Nancy Davis Reagan recognized the special prerogatives of the First Lady. She believed that the wife of a President "genuinely has the power to make a difference" and advised her successors to remember that they would "never again be in this unique position to make such a contribution." She urged them to make their opinions known either to the President or to his staff. "In spite of a White House full of people taking care of various aspects of a President's life," she said, "you're the one who knows him best. You don't give up your right to an opinion just because you're married to the President."As a result, Nancy Reagan's efforts as First Lady supported and helped her husband. Although she openly declared her intention to act as the President's sounding board, her influence in the Reagan administration amounted to more than merely serving as a ready listener who offered an occasional opinion. She closely supervised the President's schedule, played a significant role in the selection of key presidential staff and at times in the replacement of aides, most notably in helping to force out White House Chief of Staff Donald Regan in 1987. She was particularly supportive of her husband when he devoted his efforts during his second term to improved relations with the Soviet Union.

Nancy Reagan's most important policy assistance was in leading the effort to persuade her husband to acknowledge publicly that he had made a mistake in secretly approving arms sales to Iran. To this end, she invited a series of people to the White House, among them Robert Strauss, the former Democratic national chairman. Reagan at first resisted this pressure but on March 4, 1987, made a public speech apologizing for the arms sale, after which his public approval ratings rose. As he survived an assassin's bullet and then colon and prostate surgeries, Reagan acknowledged the importance of First Ladies in general, and his First Lady in particular:"First Ladies aren't elected, and they don't receive a salary. They have mostly been private persons forced to live public lives, and in my book they've all been heroes. Abigail Adams helped invent America. Dolley Madison helped protect it. Eleanor Roosevelt was FDR's eyes and ears. Nancy Reagan is my everything."Although she might have been "everything" to the President, Nancy Reagan was often a target for the media. In some cases, she created her own problems. During the 1981 recession Nancy Reagan wore designer dresses, undertook an expensive renovation of the White House, and ordered new china. She was later ridiculed for consulting with an astrologist to guide presidential scheduling—a secret until Donald Regan exposed it in a 1988 memoir in which he avenged himself against Mrs. Reagan for his firing. Mrs. Reagan had known the astrologer, Joan Quigley, in California. She had turned to her for guidance after her husband was shot, fearing that he might again become a target of a would-be assassin. Responding to stories about her clothes and high style that depicted her as "Queen Nancy" during the recession, Nancy Reagan and her aides worked to repair her image. She did so most notably at a Gridiron Dinner on March 29, 1982, where she won the plaudits of this showcase audience by doing a song-and-dance number. She also won praise even from critics by throwing the weight of her office behind her anti-drug campaign.

Her concern about drug abuse was not just for show. As First Lady of California, Nancy Reagan had been involved in anti-drug issues, as well as with the Foster Grandparent program and efforts to locate missing servicemen. On the whole, her efforts were admirable. She used her position to lobby against teen drug abuse, appearing at many school events to promote the issue. She concerned herself with both prevention and rehabilitation, and focused international attention on the topic when she spoke to an audience of first ladies from countries throughout the world at the United Nations. She also used the media and popular culture to her advantage, appearing on a popular sitcom and at a Super Bowl halftime show to discuss drug abuse. She also scheduled a celebrity White House tennis tournament to raise funds for drug rehabilitation centers.

The success of her initiative was limited, however. Although she focused attention on the issue of drug abuse, her program did little more than celebrate local efforts, nonprofit groups, and children who were winning the battle against drug addiction. In addition, Mrs. Reagan's "Just Say No" campaign encountered further criticism when the Reagan budgets slowed the rate of increase of federal funding of drug-abuse programs. Mrs. Reagan said in response that raising awareness was more important than increased funding. Nancy Reagan's openness when she was stricken with breast cancer—she decided on a mastectomy instead of a lumpectomy to remove a malignant breast tumor—focused increased attention on the desirability of annual examinations that could detect cancer in its early stages. After the presidency, when her husband became ill with Alzheimer's disease, she also tried to raise awareness about this growing malady. Throughout her long and celebrated marriage to Ronald Reagan, she was a guide and trusted friend. Without Nancy Reagan, said her closest aide Michael Deaver, there would have been neither a Governor Reagan nor a President Reagan.