Poulson's victory in the Los Angeles mayoral race came after a contentious battle in which his opponent, incumbent mayor Fletcher Bowron, claimed that the Los Angeles Times wanted to control city government and, by endorsing Poulson, would have a puppet in the mayor's office. Poulson, for his part, challenged Bowron's support for public housing, in particular a project in the area known as Chavez Ravine in Elysian Park Heights. With the support of the group Citizens Against Socialist Housing and drawing on the anti-communist atmosphere of the time, Poulson promised to end support for such "un-American" housing projects and to fire city employees who were communists or who refused to answer questions about their political activities. During his eight years as mayor, Los Angeles became the third largest city in the United States, with Poulson instrumental in leading the construction of the Los Angeles International Airport and expanding the Los Angeles Harbor. Most notably, he led the drive to lure baseball's Brooklyn Dodgers to Los Angeles. This led to what became known as the Battle of Chavez Ravine which resulted in the removal of Hispanic residents from land on which Dodger Stadium was later constructed. He helped integrate the city's fire and police departments and initiated a garbage recycling program that proved to be a factor in his defeat in 1961. Perhaps the most memorable image of his mayoral career came on September 21, 1959, when he addressed Soviet premier Nikita Khrushchev during a public ceremony. The comments came after Khrushchev had constantly touted Soviet superiority during his tour of the city by Poulson. Citing Khrushchev's phrase, "We will bury you," Poulson responded, "You shall not bury us and we shall not bury you. We tell you in the friendliest terms possible we are planning no funerals, yours or our own." Poulson received over 3,600 letters following the incident, many of them praising him for his comments. He lost a reelection campaign in 1961 to Sam Yorty, partly due to having to explain the expenses incurred by the Dodgers' franchise shift. Efforts to blunt such criticism were limited due to a severe case of laryngitis, which prevented him from responding to the invitation from local television personalityGeorge Putnam to debate Yorty on his show. Poulson never recovered from the laryngitis and his campaign never recovered from the setback.
Following the defeat, Poulson briefly returned to accounting before moving to La Jolla, California in 1962. He died in 1982.