Despite Monroe's overwhelming election to a second term, much bitterness remained about the Missouri Compromise and the Panic of 1819. Ill- feelings would last throughout his term and cause him troubles towards the end of his term.

Events in the few remaining Spanish colonies in the Americas now led Monroe to enact perhaps the seminal move in American foreign policy during the nineteenth century. Several revolutions had raged at varying intensities through the colonies and many Americans hoped Monroe would recognize the colonies as independent from Spain. Monroe, however, had resisted thus far. However, beginning around 1822, he faced growing concern that the European powers, known incorrectly as the Holy Alliance after the reshaping of post-Napoleonic Europe, might intervene, put down the rebellions and established a new foothold in the Americas. Britain, not being part of the Alliance and in fact benefiting from increased trade with the "independent" colonies, opposed the imposition of European power on the colonies and so in 1823, the British Foreign Minister suggested that America and Britain announce their opposition to European intervention. The message, coming through the minister to Britain's Richard Rush, Monroe's former attorney general, met with mixed responses in Washington. Both Thomas Jefferson and James Madison, Monroe's close confidants, strongly supported the move, seeing it as bolstering Anglo-American relations and as a smart foreign policy decision. His cabinet split, with only Secretary of State John Quincy Adams strongly demurring. After much debate and thought, Monroe decided to go one step further.

In his address to Congress in December 1823, Monroe asserted that the United States was the dominant power in the Americas. Any interference of any kind by European powers anywhere in the Americas would be viewed as hostile. Furthermore, in a statement aimed at Russian claims in Alaska and the far West, Monroe declared that as far as the U.S. was concerned, the Americas were closed to further colonization. His assertion of power would come to be known as the Monroe Doctrine and firmly established the U.S. as an independent nation with a clear foreign policy.

Admittedly, at first it had little weight and received little notice among the European powers. Britain's declaration of opposition to European interference was what prevented Spain or any other nation from pushing their colonies in America–not the Monroe Doctrine. However, over time, the Monroe Doctrine came to define nineteenth century thinking in America. By treating the U.S. as a world power, worthy of attention, Monroe in some respects made the U.S. worthy of attention.

Monroe ranks among America's great presidents if for no other reason than the Monroe Doctrine. His actions as president were often indecisive, preferring compromise to direct action and deferring to the legislative branch in matters of controversy. The Doctrine is, of course, a notable exception.

His term came to a close in 1825, after one final battle stemming from the Missouri issue. Many of Monroe's close friends and colleagues began jockeying for position to run for president by late 1823 and without a clear successor the race turned very bitter. An easy target for aspirants was the current administration; Monroe found his treatment of everything from the Panic of 1819 to the Missouri Compromise under fire. The jockeying even hurt Monroe's much- vaunted foreign policy when the Senate, led by supporters of William Crawford, amended a treaty that cut back on the international slave trade–a move that so angered the British they refused to ratify the amended treaty, thereby ending any hope of an Anglo-American reconciliation. Opponents of John C. Calhoun also stopped a plan to ease treatment of Indians, since Indian affairs then fell under the War Department's domain.

John Quincy Adams won the presidency in 1826 and Monroe prepared to leave public life. His wife, however, was too ill to travel and so they lived on in the President's House for three weeks before she regained her strength. Monroe returned to his estate in Virginia.

He retired from the presidency completely broke. He spent much of his remaining years arguing for the government to reimburse him thousands of dollars in expenses during his life-long public career; some of his filings requested funds dating back to his first mission to France. The new administration balked at the high cost, and many congressmen found his claims outrageous. It was not until 1831 that Congress granted him thirty thousand dollars in back expenses, roughly half his original claim. Although he served on the board of trustees for the University of Virginia, his last public office was as a presiding officer of the Virginia constitutional convention.

Monroe's wife died in 1830 and he moved to New York City to live with his daughter. His last months were devoted to writing his dry and uninteresting autobiography–a project that remained unfinished at his death.

During 1831, he steadily weakened from tuberculosis and died on July 4, 1831–the third of the first five presidents to die on Independence Day. Originally buried in New York, his body was moved to Richmond in 1858, just before the Civil War–a conflict that stemmed directly from his Missouri Compromise.

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