Smith was nominated for U.S. Attorney General shortly after Reagan's victory in the 1980 United States presidential election, assuming the title on January 23, 1981, and serving until February 25, 1985.

His father of the same name was president of Boston-based Mexican Telephone and Telegraph Co. From 1942 to 1946, Smith served in the United States Naval Reserve, reaching the rank of lieutenant.

He also designed an immigration and refugee policy, announced a more lenient attitude towards corporate mergers in order to make government more responsive to the concerns of business, opposed anti competitive practices, and modified the Freedom of Information Act of 1966, among many other initiatives.

President Ronald Reagan said this about Smith during a speech announcing the Federal Initiatives Against Drug Trafficking and Organized Crime; A few months ago Attorney General William French Smith and his staff, in collaboration with the Treasury Department, put together final plans for a national strategy to expose, prosecute, and ultimately cripple organized crime in America.

This requirement, although simple and inexpensive, will establish a formal mechanism through which the Justice Department will take a yearly inventory of its efforts in this area and report to the American people on its progress.

[2] Smith also played a role in the nomination of Sandra Day O'Connor, the first woman to serve on the United States Supreme Court.

[3] Judicial analyst Steven Brill gave Smith credit for gaining control of the Justice Department mega-bureaucracy and for cleaning up the corruption-plagued Drug Enforcement Administration.

During his tenure as Attorney General in President Reagan's cabinet from 1981–1985, Smith facilitated a deal where the U.S. and Italy agreed on a strategy to combat organized crime and narcotics trafficking.

He also served on the boards of major corporations and was named chairman of the Ronald Reagan Presidential Library Foundation, where he was instrumental in locating site for the attraction.

Reagan appointed Republican and former Senator John Tower of Texas, former Secretary of State Edmund Muskie, and former National Security Advisor Brent Scowcroft.

A one-hour memorial funeral service, attended by 250 people, was held on November 2 at the Community Church of San Marino, where he was eulogized by Reagan and others.

His second wife, Jean Webb Vaughan Smith, who championed volunteerism as national president of the Association of Junior Leagues, died in 2012, aged 93.