He resigned on September 9, 1968 to accept an appointment by governor Nelson Rockefeller to fill the vacancy caused by the assassination of United States Senator Robert F. Kennedy on June 5, 1968.

He won a special election on May 26, 1959 as a Republican to the 86th United States Congress to fill the vacancy caused by the death of Daniel A. Reed.

[11] In the Senate, Goodell authored and sponsored a large number of bills, including several to provide conservation and development aid to small towns and rural areas.

Many small upstate New York communities without municipal sewage systems built them with the aid of federal matching funds provided by Goodell's legislation.

[citation needed] Along with Oregon senator Mark Hatfield, Goodell was among the loudest anti-Vietnam War Republican voices.

Goodell ran under the slogan "Senator Goodell—He's too good to lose" and received the nomination of the Liberal Party as well as that of the regular Republican organization, an electoral fusion allowed under New York law.

A television ad aired by Goodell's 1970 campaign compared him to opponents Richard Ottinger and James L. Buckley as "the lightweight, the heavyweight and the dead weight."

[15] They had five children: Bill, a hedge fund executive;[16] Tim, a senior vice president for the Hess Corporation;[17] Roger, the commissioner of the NFL; Michael, a Pilates instructor and Jeff, the former head of the Upper School of Saint Mary's Hall in San Antonio.

[20] Goodell married Patricia Goldman (1942–2023), a congressional caucus director who later sat on the National Transportation Safety Board, in 1978.