After mustering in May 1898 for service in the Spanish–American War, the regiment trained in Nebraska and at Camp Merritt in California before leaving for the Philippines in June.

In April, the regiment fought at the Battle of Quingua, where its commander, Colonel John M. Stotsenburg, was killed.

On July 1, the regiment boarded the steamship SS Hancock, which brought the men back to the United States, where they mustered out on August 23.

[7] While at Camp Merritt, an order was made to increase the size of the regiment's companies, and a few men were sent back to Nebraska for further recruiting.

[9] The regiment left for Manila on June 15,[2] traveling on the steamship SS Senator, with three other troopships in the convoy.

[12] The American troops occupied a position established by local Filipino rebels, and at 21:40 on August 2, the 1st Nebraska came under fire for the first time.

[14] When American troops occupied Manila on August 13 in an affair partially arranged with the local Spanish commander, the 1st Nebraska was one of the units that advanced into the town.

[15] American troops performed occupation duty in the city, with the First Nebraska policing the waterfront district near the customs house.

[16] Tensions remained between the Americans and the Spanish and with the Filipino rebels under General Emilio Aguinaldo, who desired independence for the Philippines.

[18] Bratt was sent home due to illness in September, and John M. Stotsenburg was promoted to colonel to command the regiment on October 4.

The losses to illness were partially offset by the arrival in late November of the additional recruits that had been authorized in June.

[19] In December, the Treaty of Paris ended the Spanish–American War,[1] and the United States signaled that it intended to keep the Philippines as a colonial possession, although Aguinaldo and his followers still desired independence.

[23] Filipino soldiers did not answer to American sentinels, and Private William W. Grayson of the 1st Nebraska fired a shot.

Part of the regiment helped a South Dakota unit capture a bridge, and later in the action, the 1st Nebraska routed the left side of the Filipino line.