Dark, intense, and wielding an imposing physique and manner, Boothe is an underutilized resource of American films and TV. His breakthrough theatrical performance was in the Broadway production of James McClure's one-act comedy, "Lone Star". Impressively convincing as ambiguous patriarchs, Boothe appropriately gained widespread notice playing the Reverend Jim Jones in the two-part CBS docudrama, "Guyana Tragedy: The Story of Jim Jones" (1980). Boothe won a richly deserved Emmy for his towering performance as the charismatic minister who led the settlers of Jonestown, Guyana to mass suicide in 1978. He was the only performer to appear at the 1980 Emmy awards ceremony during an actors' strike which had resulted in a near total boycott. During his acceptance speech, Boothe admitted that he might be committing professional suicide by showing up.

Tough guy directors of "masculine" action fare have shown their appreciation of the power of Boothe's performances. Walter Hill cast him in lead roles in "Southern Comfort" (1981) and "Extreme Prejudice" (1987) while John Milius gave him a supporting role in "Red Dawn" (1984). Boothe's most impressive film work may be in "The Emerald Forest" (1985), John Boorman's quasi-mystical ecological tale of the South American rain forests, where he plays an American engineer overseeing the construction of a dam when his seven-year-old child is spirited away by a "primitive" Amazon tribe. The father spends the next ten years searching for his son and experiences a spiritual awakening after finding him. Boothe returned to more conventional action roles in "Rapid Fire" (1992), opposite the late Brandon Lee, and as Curly Bill Brocious in the popular revisionist Western "Tombstone" (1993).

In 1995, he played two quite different men: In Peter Hyams' "Sudden Death", Boothe was the ringleader of a gang of terrorists who threaten to blow up a hockey arena while Oliver Stone chose him to portray Alexander Haig in Stone's controversial biopic "Nixon" (1995). The actor reteamed with Stone on the thriller "U-Turn" (1997) and portrayed a mentor of African-American navy diver Carl Brashear in "Men of Honor" (2000). Boothe experienced something of a career revival when he appeared in a recurring role as the ruthless high class gambling joint owner Cy Tolliver in the accalaimed HBO Western series "Deadwood" (2004 - ), followed by an effective cameo as the corrupt Senator Roarke in director Robert Rodriguez and writer-artist Frank Miller's visually arresting adaptation of Miller's crime noir comic book series "Sin City" (2005).