Relations between the United States and Spain were already strained over Cuba when the battleship USS Maine mysteriously exploded in Havana Harbor on February 15, 1898. Spain had been accused of cruelly crushing rebels in its Cuba and Philippine colonies, and newspapers across the U.S. clamored for retribution.

The sinking of the Maine and the hysterical newspaper reports that followed led Congress to declare a state of war with Spain on April 21, 1898. Four days later, President William McKinley asked Oregon for a regiment of infantry, with a strong preference that the National Guard be used to fill the request. By May 11, Oregon had organized and mustered in the Second Regiment, Oregon U.S. Volunteer Infantry. On May 25, the regiment embarked at San Francisco and sailed for the Philippines. It was the first time that members of the Oregon National Guard fought on foreign soil.

Oregon units took part in the peaceful surrender of the island of Guam on June 21. The Oregon regiment then provided the first U.S. Army unit to land at the Philippines and the first unit to enter the Walled City of Manila. The regiment took part in the surrender of the Spanish army in Manila on August 13. On August 16, the war with Spain came to an end, and Oregon's regiment took up provost guard duty, playing the role of police in the city of Manila. But the Oregon Volunteers' service to the war was not yet over.

On February 4, 1899, Philippine insurgents attacked U.S. troops in Manila. For the next four months, Oregon troops fought in five campaigns and forty-two battles, engagements, and skirmishes. Sixteen Oregonians were killed in action or died of wounds, forty-eight died of other causes, and eighty-eight were wounded in action. 

Three members of the regiment were awarded the Medal of Honor for heroism: Private Edward E. Lyon of Portland, Private Frank C. High of Jacksonville (later Ashland), and Private Marcus Robertson of Hood River. On May 13, 1899, Private Lyon, with eleven other scouts, charged over a distance of 150 yards and routed about 300 of the enemy. Three days later, the same scouts led an advance across a burning bridge and engaged more than 200 insurgents. Privates Robertson and High were cited for decisive action and teamwork during the engagement. 

The regiment sailed for home on June 14, 1899. Before its departure, Major General H.W. Lawton told the soldiers: "You have nobly earned the reputation of being among the best soldiers of the American Army." Oregon National Guard troops returned to the Philippines in 1945 to help free the islands from Japanese occupation.