Founded in 1865, the town began as nothing more than a large Spanish Rancho, and was called Aqua Negro Chiquita. Sometime around 1890, it took a new name honoring a chapel built by Don Celso Baco who named it for his wife and Saint Rose of Lima, the first canonized Saint of the New World. Guadalupe County was created by the territorial legislature in 1891 with Puerto de Luna as the county seat. Santa Rosa remained a minor community until the Chicago, Rock Island & Pacific Railroad steamed into town in 1901, then became an important transportation hub of the area. Just two years later, Santa Rosa became the Guadalupe County seat.
When Route 66 was completed through Santa Rosa in 1930, transportation services again increased in the city. During the days of early Route 66, after travelers had tired of the long, hot, dusty miles, Santa Rosa became known as a welcome and well-known oasis in the desert. Travelers arrived in Santa Rosa to eat, rest, and perform car repairs, if necessary, at the many motels, cafes and service stations that lined the highway.
The old road ran into town past the 81-foot-deep Blue Hole and Park Lake, a motorist campground and source of water during the Depression. Scenes in Rudolfo Anaya's award-winning novel, Bless Me, and John Steinbeck's, Grapes of Wrath, took place on Route 66 at the Pecos River Bridge.
In 1940, when Steinbecks epic novel, Grapes of Wrath, was made into a movie, director John Ford used Santa Rosa for the memorable train scene, where Tom Joad (Henry Fonda) watches a freight train steam over the Pecos River railroad bridge, into the sunset.