The story of Dr. T. Lawrence Shannon, a defrocked Episcopal minister, played by Richard Burton, Night of the Iguana(1964) is set in Mexico in 1940. Like many of his other works, Night of the Iguana, grew out of one of Williams' experiences abroad. Williams traveled to Acapulco in 1940 and witnessed the heat, listened to news of the war, and saw the infiltration of the Nazi's into the city. He also remembered some young children capturing a small iguana, tying it up, and fattening it for eating.

The film evolved from the 1946 short story, and its corresponding 1960 play. In the film, Williams used his memory of the captured iguana to symbolize Shannon, a former clergyman trapped by rapacious women who wish to consume him for different reasons. In the end, Shannon realizes that he will never return to the ministry, but finds some relief when, like the iguana, he is released.

Famed director John Huston filmed on location in Puerto Vallarta for three months. The cast included such luminaries as Burton, Deborah Kerr, and Ava Gardner. They endured three months of harsh conditions and two serious accidents. One, in particular, endangered Burton when the bus he and several actors were on almost fell off a mountainside cliff.

The film received both popular and critical praise. It won the 1964 Academy Award for "Best Costume Design," and also received nominations for "Best Actress in a Supporting Role" (Grayson Hall), "Best Art Direction- Set Direction, Black-and-White," and "Best Cinematography, Black-and-White."