In 1836, Tyler was instructed by the Virginia legislature, which was controlled by supporters of Jackson, to vote for a resolution expunging the censure of Jackson from the Senate record.  Tyler refused, and rather than comply, resigned his senate seat. This gave rise to the Whigs that the disaffected Democrat would be a strong candidate for vice-president.  Even though the Whigs lost the election in 1836, Tyler did make a good showing, gathering 47 electoral votes.  

In 1838, Tyler won the election to the Virginia legislature as a Whig, and received the honor of being chosen as Speaker-of-the-Lower House. The following year he was unsuccessful for his bid for re-election to the US Senate, and the voting ended in a temporary deadlock with no one selected to fill the vacancy.  

In December 1839, at the Whig National Convention in Harrisburg, Pennsylvania, Tyler was nominated for Vice President as the running mate for William Henry Harrison.  The "Tippecanoe and Tyler Too" victory made Tyler Vice President, and one month later to his astonishment and that of others, he was President.  

It was Tyler's plan as Vice President to take no part in discussions concerning cabinet appointments and as well to play an unobtrusive role in the government.  These plans of course were short-lived, as he was roused from his bed at dawn on April 5, when he learned of the news of Harrison's death. 

While Tyler made it clear who was boss, Henry Clay and other Whig leaders were confident they could control him by the majority they held in both houses.  He refused to accept that all decisions be put to a majority vote, saying, "I can never consent to being dictated to." When the special session convened in May to address the national economic crisis, Clay began pushing through legislation for a new national bank, even though Tyler warned that he believed this to be unconstitutional.  When Tyler vetoed the measure that August, Clay was enraged because he did not have the votes to override the veto.  It was this event that gave rise to the resignation of his cabinet, except Webster, and two days later, the Whig party expelled Tyler. 

Beleaguered, Tyler replaced his Cabinet with conservative Democrats, starting a chain of appointments that gave Tyler the distinction of having more Cabinet changes that any other single-term President.  Congress continued to pass legislation that it knew Tyler would accept.  In the summer of 1842, Tyler twice vetoed bills that called for higher tariffs, bringing cries from the Whigs that he should be impeached. With the public treasury almost empty, he signed a tariff measure to raise needed revenue, but this did not stop the impeachment attempt. This was brought to a vote in the House in January 1843, but was defeated 27 to 83.  

Tyler's administration was more successful in foreign relations than domestic affairs. One of his achievements, with the help of Daniel Webster was the conclusion of the Webster-Ashburton Treaty that settled a long-standing dispute over the boundary between Maine and Canada. Another achievement was the 1844 treaty with China that opened trade with American merchants. 

In February 1844, an unusual tragedy struck his administration. President Tyler and a large party of friends were on a cruise down the Potomac River on the newly powered steam warship Princeton.  Suddenly one of the ship's guns exploded, killing several of the guests, including Secretary of State Abel B. Upshur and Secretary of the Navy Thomas W. Gilmer.