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Adams served as Secretary of State in the Monroe's cabinet for Monroe's entire presidency (from 1817 until 1825.) For the most part, his views concurred with those of Monroe. As Secretary of State, Adams negotiated the Adams–Onís Treaty (which acquired Florida for the United States), the Treaty of 1818, and even though it bears the president's name, most historians give Adams credit for writing the Monroe Doctrine. Many historians regard him as one of the greatest Secretaries of State in American history.
When Monroe became president, Florida was still a Spanish territory but with no Spanish presence to speak of. It became a refuge for runaway slaves and native Americans. In response to complaints from southerners about concerns for their safety, Monroe sent in General Andrew Jackson to pushed the Seminole Indians south. Jackson also executed two British merchants who were supplying weapons, he deposed one governor and named another, and he left an American garrison in occupation. President Monroe and all of his cabinet except for Adams, believed that Jackson had exceeded his instructions. It is ironic that Adams was the lone supporter for Jackson's actions, since the two men would later become bitter enemies. But Adams argued that since Spain had proved incapable of policing her territories, the United States was obliged to act in self-defense. Adams was so able in his justification of Jackson's conduct that he silenced protests from either Spain or Britain. Congress refused to punish Jackson and Adams used the events that had unfolded in Florida to negotiate the Florida Treaty with Spain in 1819 that turned Florida over to the U.S. and resolved border issues regarding the Louisiana Purchase.
At the time there was an ongoing boundary dispute regarding the Oregon territory (one which would remain unsettled until the presidency of James K. Polk.) Adams tried to negotiate a settlement with England to decide the border between the western United States and Canada. In the Treaty of 1818, Article III provided for joint control of land in the Oregon Country for ten years. Both could claim land and both were guaranteed free navigation throughout. This, as well as the Rush–Bagot Treaty of 1817, marked the beginning of improved relations between the two nations as well as better relations between the U.S. and Canada (which was still a British colony).
By the time Monroe became president, several European powers, in particular Spain, were attempting to re-establish control over South America. On Independence Day 1821, in response to those who advocated American support for independence movements in many South American countries, Adams gave a speech in which he outlined the administration's policy on independence for propspective South American nations. He said that American policy was moral support for independence movements but not armed intervention. Adams stated:
"America goes not abroad in search of monsters to destroy, lest she involve herself beyond power of extrication, in all wars of interest and intrigue, of individual avarice, envy, and ambition, which assume the colors and usurp the standard of freedom. The fundamental maxims of her policy would insensibly change from liberty to force."
From this resulted what came to be known as the Monroe Doctrine, which was introduced on December 2, 1823. It stated that further efforts by European countries to colonize land or interfere with states in the Americas would be viewed as acts of aggression requiring U.S. intervention. The United States wished to avoid having any European power take over Spain's colonies. It became a defining moment in the foreign policy of the United States and one of its longest-standing tenets, and would be invoked by many U.S. statesmen and several U.S. presidents, including Theodore Roosevelt, Calvin Coolidge, Herbert Hoover, John F. Kennedy, and Ronald Reagan.
Monroe left office on March 24, 1825. He was pleased to see his Secretary of State as the new president. Monroe had racked up many debts during his years of public life and had sold off his Highland Plantation to pay them. Throughout his life, he was not financially solvent, due in part to a ne'er-do-well brother for who he accepted financial responsibilty, and also due to his wife's poor health made matters worse. He and his wife lived in Oak Hill, Virginia, until Elizabeth's death on September 23, 1830. In August 1825, the Monroes had received the Marquis de Lafayette as their guest and also his friend the new President John Quincy Adams. According to one biographer, Monroe was anxious to discuss foreign affairs with the new president, and Adams recorded some distress as seeing how Monroe's health was deteriorating.
After his term in office ended, Adams visited Monroe once again, in April 1831. By this time Monroe was a widower and was living at his daughter's home in New York. Adams found Monroe to be alert and eager to discuss the situation in Europe, but in ill health. Adams cut the visit short when he thought he was tiring Monroe. Monroe died three months later from heart failure and tuberculosis on July 4, 1831.