On December 31, 1845 a revolution in Mexico brought Mariano Paredes to power. Polk hoped he would bring a more constructive approach to the bargaining table. The American negotiator had been rejected by the previous Mexican government because his credentials said that he was a minister and the government had requested a commissioner. Polk also hoped the problems of holding together a revolutionary government would help keep Paredes concerned with internal problems and push him towards quickly settling the external disputes. However, Paredes did nothing of the sort and sent the American minister back to the U.S.

Polk ordered a naval force off the Mexican coast and General Zachary Taylor moved his army up to the bank of the Rio Grande which Polk claimed as the Texas-Mexico border, although it was about 100 miles past the commonly accepted border of Mexico and Texas. On March 24, 1846 Taylor arrived at the Rio Grande, opposite the Mexican town of Matamoras. Two weeks later, the Mexican general on the other side of the river informed Taylor that his presence was an act of war. The situation quickly spiraled out of control, as the two governments refused to open lines of communication and the situation escalated too quickly for communication with the capitals to be relevant. The Mexican general insisted that Taylor withdraw within twenty-four hours or face attack. Taylor accepted and moved to blockade the Rio Grande, an undeniable act of war. Mexico asked Taylor to lift the blockade, and when Taylor again refused to comply, they were left with the choice of leaving the soldiers in Matamoras to starve or fight their way out. On April 23, Paredes declared that a state of war existed. War had begun. Unfortunately, due to the lack of fast communications, Polk was not aware of any of these happenings until May 9.

The same day Parades declared war a country away, Congress nullified the joint occupation treaty with England in regards to the Oregon territory. Polk had waited impatiently for weeks. In doing so, he proffered that, with the Senate's okay, he would still compromise on the 49th parallel. England quickly agreed to the compromise and on June 16, 1846, Polk announced to his cabinet the Senate's concurrence with the proposal and on August 5, the Senate ratified the new border with England–the border that remains to this day.

On Saturday, May 9, Polk finally received word of the Mexican War. He quickly prepared a message to Congress to be delivered on Monday, May 11. The House followed the president's message by declaring war on Mexico, but the Senate held up passage until Tuesday evening. The Secretary of War immediately dispatched General Winfield Scott, the highest-ranking army officer, to the war but Scott, a politician to the core, was reluctant to leave Washington. Polk wanted the war prosecuted as quickly as possible, and he asked the Senate to promote Taylor to head of the army.

Polk's approach to the war differed from that of his fellow politicians. He saw it as something to be won quickly and as painlessly as possible, while most others approached it as a way to reward old friends with commissions and command positions. Polk announced, however, that commissions would be granted based on competence and would be split between Democrats and Whigs. This announcement bolstered a growing resentment towards Polk's fairness among other Democrats, who had hoped for the spoils of past administrations. In return, Polk found his measures blocked by angry congressmen and his proposals tied up in parliamentary procedure on Capital Hill.

Meanwhile, the war progressed. Polk assigned Spanish-speaking Catholic priests to the Army so that they could pacify the Mexicans during the coming invasion by explaining the U.S.'s respect of the Church. The Mexican leader Santa Anna, exiled to Cuba after Parades's revolution, came to the U.S. with an offer of support: If allowed back to Mexico and restored to power, he would gladly sell New Mexico and California to the U.S. But when the U.S. government helped Santa Anna back into Mexico and he restored himself to power, he promptly rejected the U.S. appeals.

Polk tried to offer Mexico two million dollars as a down payment for New Mexico and California. However, Congress blocked the bill amid controversy over the Wilmot Proviso, an amendment which stipulated that slavery would be illegal in any territory given over by Mexico. Obviously, the clause met with serious objections from the Southern congressional representatives and the bill was tabled. Polk's attempts to end the war using money not lives had been rejected.

Taylor had become obsessed with using the war to define himself as the next George Washington or Andrew Jackson, the heroes of the Revolutionary War and the War of 1812 respectively. Even as the war began, he allied himself with the Whigs and his anti-administration letters began to turn up in American newspapers. Worse still, Polk could not count on Taylor to follow orders. Instead of capturing Monterey, he granted the Mexicans a two-month truce under which to withdraw.

Polk wanted Taylor to capture the northern territories while other troops occupied California. Then Scott would station troops at Vera Cruz and march inland to Mexico City. Late in January 1847, however, he wrote in his diary, "I am responsible for the conduct of the war, yet Congress refused to give me a commander in whom I have confidence and I am compelled to employ officers whom the law has provided, however unfit they may be." Taylor continued to disobey orders and even published a letter in one newspaper laying out the government's secret invasion plans at Vera Cruz. Despite Polk's orders prohibiting such a battle, Taylor's victory at Buena Vista made him a national hero.