Senator Kennedy's overwhelming re-election as Senator in 1958 put him on everyone's short list of possible candidates for the Democratic Presidential nomination in 1960. In 1957 alone, he received over 2,500 requests for speaking engagements from all parts of the US. He delivered 144 speeches, in 47 states. Opinion polls of Senator Kennedy were also very favorable; with 64% of Americans in 1958 believing Kennedy had the " background and experience to be President" .

Despite his overwhelmingly favorable statistics, Kennedy's nomination for president was far from assured. Adlai Stevenson, the two-time failed candidate of the liberal wing of the Democratic Party, was as popular as Kennedy among the party faithful. Kennedy tried to get Stevenson's endorsement, but failed. Kennedy then began a two-pronged effort to achieve the presidential nomination. He picked up the pace of his speaking engagements, spending days crisscrossing the US. At the same time, Kennedy recruited his brother-in-law, Stephen Smith, to conduct n effort to reach out to party leaders. With only 17 primaries, Kennedy could not hope to gain the presidential nomination with the support of the established leadership of the Democratic Party alone.

On January 2nd, 1960, John F. Kennedy officially announced he would seek the Democratic nomination for the Presidency of the United States. His announcement was timed to get the maximum news coverage and it did. Kennedy made clear in his announcement that he was not running for Vice President, despite his relative youth. Kennedy stated unequivocally that he would not accept the nomination as Vice President From the moment he entered the race, Kennedy was clearly the candidate to beat, though at first, party regulars were skeptical of his chances. The first primary was in New Hampshire, where Kennedy won 85% of the vote (despite it being viewed as a " Protestant" state and likely to be worried about Kennedy's Catholicism.) Kennedy ran unopposed in a series of other primaries. His first deeply-contested primary was in Wisconsin. His opponent was Hubert Humphrey, the Senator from Minnesota. Humphrey was well known in Wisconsin and thus a formidable opponent. Kennedy campaigned for six weeks, in late February to early April with Kennedy's entire family taking part. Their hard work paid off on April 5, when Kennedy scored a victory, receiving 56.5% of the vote. While Wisconsin was also largely a Protestant state, Kennedy owed a significant part of his victory to his overwhelming support in Catholic districts. As a result, he still had to prove that he could win in a state without a large Catholic population. That opportunity occurred in West Virginia, whose electorate was only 4% Catholic.

Kennedy met the issue of his Catholicism head-on. On the first day of the campaign in Charleston he stated, " I am a Catholic, but the fact that I was born a Catholic does not mean that I can€™t be the President of the United States. I am able to serve in Congress and my brother was able to give his life, but we can€™t be President? " Kennedy campaigned endlessly in West Virginia. His wife campaigned successfully there as well, clearly connecting with the people. Kennedy out-campaigned and outspent Humphrey. The result was Kennedy's landslide victory receiving 60.8% to 39.2% for Humphrey.

The Democratic convention opened in Los Angeles on July 11th. Kennedy arrived with a commanding lead. His major opponent was Senate Majority Leader, Lyndon Johnson. However, a " draft Stevenson" movement seemed to be picking up steam, as the convention got under way. This movement was in a sense a " stop Kennedy" movement, for any vote for Stevenson would be a vote that Kennedy would not get, and that might deny Kennedy the nomination on the first ballot. The feeling in Los Angeles was that the support for Kennedy was soft, and thus if Kennedy did not win on the first ballot, his support might fade away. Therefore, all of the Kennedy camp's efforts were directed to a first-ballot victory and Kennedy did indeed win on the first ballot.

Kennedy now had to choose a Vice President. Kennedy recognized that he needed the support of Lyndon Johnson, who was the Senate Majority Leader to govern effectively. To heal the wounds created by the campaign, he decided to offer Johnson the option of running for Vice President. Much to Kennedy's surprise, Johnson accepted the offer. Senator Johnson was extremely helpful in the general election, campaigning effectively in the South and bringing the electoral votes of Texas into the Kennedy column. The general election was a closely-run race between Jack Kennedy, the Senator, and Richard Nixon, the sitting Vice President. Kennedy's major campaign theme was " the need to get the country going again" . Typical of his campaign speeches Kennedy stated: " I have premised my campaign for the Presidency on the single assumption that the American people are uneasy at the present drift in our national course, that they are disturbed by the relative decline in our vitality and prestige, and that they have the will and the strength to start the United States moving again. "

Other campaign themes included the "missile gap", highlighting that the United States was falling behind the Russians in missile production.

The most important milestones in the campaign were the series of debates between Nixon and Kennedy. Kennedy immediately gained points for being on the same platform as Nixon, and holding his own. In the first debate, Nixon's make-up was misapplied and the studio was too hot. As a result Nixon came across looking tired and uncomfortable, compared to the young vigorous look of Senator Kennedy. After the debates, the crowds for Kennedy grew. Wherever his motorcade went, the crowds would jam the streets. In October, Martin Luther King Jr. was arrested in Georgia. Kennedy was informed of the event. Sargent Shriver, Kennedy's brother-in-law suggested Kennedy call Mrs. King to express his support, which he did almost immediately. Robert Kennedy then intervened by calling the judge involved, and securing King's release. This brought Kennedy additional support in the African American community.

Finally, Election Day arrived. The margin of the popular vote was one of the narrowest in US history. It took until the middle of the next day to declare Kennedy the winner in Minnesota and for Nixon to concede, making Senator Kennedy, President-Elect Kennedy. He had won by just 113,238 votes though his electoral victory was a more decisive: 303-219 votes.