On the 25th of July, 1812, the first blood of the War of 1812 was shed in a skirmish not far from Detroit. For two years the Second Infantry found itself constantly engaged against hostile Indians who had been incited by British agents to harass the American settlements. During this period, Captain Zachary Taylor, later commander of the First Regiment and 12th President of the United States, won his first fame commanding a company of the 7th Infantry in the successful defense of Fort Harrison, Indiana.

Also, during this period the Regiment was erroneously awarded campaign streamers for Canada and Lundy's Lane. None of the parent regiments of the present 1st Infantry were present in that theater of operations. The Department of the Army has ruled, however, that once streamers have been awarded they will not be taken away Later in the war, on 25 July 1814, the Regiment fought in the Battle of Niagara and six days later participated in the siege of Fort Erie.

The first action in the south was against the Creek Indians who split under the leadership of Chief Tecumseh into two camps. One party of the nation remaining at peace and the other allying themselves to the British cause. In a series of battles the parent regiments of the First Infantry helped to pacify the Creek resistance and to eliminate British supply points in Spanish Florida. In carrying out this latter mission, Mobile Alabama had been seized. The Second Infantry was given the mission of garrisoning Fort Bowyer, which controlled the entrance to Mobile Bay.

In the summer of 1814, a British/Indian force from Spanish Pensacola attacked the small 130-man garrison of the Second Infantry Regiment at Fort Bowyer. The British landed 130 Marines and 600 Indians to seal off the peninsula on which the fort stood. The fleet then took station and began the bombardment. After four days, American losses were four killed and four wounded. The British loss was 160 dead, 70 wounded in the fleet, and two killed on land. In addition, one artillery field piece was destroyed, one British ship was sunk, and another was so heavily damaged it had to withdraw. The first British thrust on New Orleans had been thwarted.

Following this action, General Andrew Jackson assembled a force that included elements of the Third and Forty-Fourth Infantry and seized Pensacola, ending that city's use by the British. The British task force that had burned Washington was in the Gulf of Mexico and was poised to seize New Orleans. Their landings started on 23 December 1814. In a bold coup-de-main, General Jackson immediately attacked. In an action on 24 December, spearheaded by the Seventh and Forty-Fourth Infantry Regiments, the British force was so exhausted that it went over to the defense for three critical days. The Seventh Infantry remained engaged with the enemy while the rest of the army went into position in front of New Orleans and reinforcements were sent up.

On 28 December, the British resumed their advance. To meet them were both the Seventh and Forty-Fourth Infantry Regiments, covering the critical right flank of the American force, anchored on the Mississippi River. An attempt by the British to by-pass Jackson and ascend the Mississippi River towards New Orleans, was stopped by the garrison of Fort St.·Phillip, manned in part by two companies of the Seventh Regiment.

The British army and fleet that had been mauled at New Orleans licked their wounds and turned angrily on Fort Bowyer. Here in early February, the enemy landed 5,000 men with strong artillery support. Thirteen enemy vessels took position off shore. After considerable efforts by British engineers, this overwhelming force put itself into position to lay siege to the tiny garrison. Recognizing their plight, the command hauled down the fort's colors and surrendered. A board of inquiry after the war upheld the decision to surrender as proper.

By the end of the war the Regiment had participated in eleven major land battles, culminating in the glorious victory of New Orleans.