Ziegler attended Concordia Lutheran School and graduated the 8th grade in 1953. He graduated from Dixie Heights High School in Fort Mitchell, Kentucky. He first attended college at Xavier University in Cincinnati. He transferred to the University of Southern California in 1958 and graduated in 1961 with a degree in government and politics. While at USC, he was initiated into the Sigma Chi fraternity. He met future Watergate scandal participants Dwight Chapin, Donald Segretti, and Herbert Porter at USC.
In 1969, when he was just 29, Ziegler became the youngest White House Press Secretary in history. He was also the first Press Secretary to use the White House Press Briefing Room when it was completed in 1970. Historically, White House press secretaries had been recruited from the ranks of individuals with substantial journalistic experience, such as Stephen Early and Pierre Salinger, raising the question of whether Ziegler was hired less for his journalistic achievement than for perceived loyalty to what became an inner circle in the White House.
He was the White House press secretary during the political scandal known as Watergate. In 1972, he dismissed the first report of the break-in at the Watergate Hotel as the discussion of a "third rate burglary attempt", and repeatedly dismissed the reports by Bob Woodward and Carl Bernstein in The Washington Post, but within two years Nixon had resigned under threat of impeachment. Ziegler, for his part, apologized to The Washington Post for having earlier been so dismissive.
During a Veterans of Foreign Wars convention on August 20, 1973, Nixon was photographed angrily pushing Ziegler towards a crowd of reporters. The president was incensed that Ziegler was not doing enough to keep members of the press away as Nixon entered the convention hall.
In 1974 Ziegler became Assistant to the President. Particularly in the period following the resignations of such senior administration officials as Bob Haldeman and John Ehrlichman, Ziegler became one of Nixon's closest aides and confidants. During the impeachment process against Richard Nixon, he defended the President until the bitter end, urging Nixon not to resign, but rather fight conviction and removal from office in the Senate. During the unfolding political scandal, Ziegler himself appeared before Congress at least 33 times.
Unlike many other former aides after President Nixon's resignation in 1974, Ziegler remained very close to him. Ziegler was on the airplane that Nixon took to Marine Corps Air Station El Toro, near San Clemente, California, as Gerald Ford was sworn into office.
On November 12, 1999, Ziegler was due to participate by telephone in a television panel discussion that included several former Nixon and Ford aides, including his successor as White House Press Secretary, Jerald terHorst, who had resigned in protest at President Ford's pardon of Nixon. However, Ziegler's feed failed to hook up for the session, which went on without him.
In 1988, Ziegler became president and chief executive of the National Association of Chain Drug Stores, living in Alexandria, Virginia. He previously served as President of the National Association of Truck Stop Operators. He was described by leading truck stop advocate William Fay as "a significant factor in expanding the travel plaza and truckstop industry's presence in the nation's capital." Hay further credited Ziegler as having achieved "great strides in membership recruitment and expansion of member services." 
In 1961 he married Nancy Plessinger, with whom he had two children, Cindy and Laurie.
Ziegler appears in the 1976 film All the President's Men as himself in archival news footage. He is portrayed in the 1995 Oliver Stone film Nixon by David Paymer. The West Wing character Toby Ziegler was named after him.
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