On his first trip, Becknell loaded manufactured goods from Missouri onto a mule train to trade for furs, gold, silver, and other goods in New Mexico. However, by his third trip Becknell had found a passable wagon route, thus beginning the many wagon trains heading to the southwest.  Credited as the "Father of the Santa Fe Trail,” Becknell continued to make multiple trips along the trail, profiting enormously on his daring travels. Soon, many traders, as well as the military, were traveling the route.

Two routes soon developed along the trail, the Mountain Route and the Jornada Route. Both routes followed the same path from Missouri, traveling west to the Arkansas River and following the river into southwest Kansas. For many years, the only trading post between Independence, Missouri and Santa Fe, New Mexico was in Council Grove, Kansas, some 130 miles from Independence and over 650 miles from Santa Fe.

At Fort Larned, Kansas the trail split into two branches. The Mountain Route was longer but not quite as dangerous, with fewer warlike Indians and more water along the route. This branch traveled about 230 miles between Fort Larned and Bent's Fort near present-day La Junta, Colorado, continuing to follow the Arkansas River before turning south through the Raton Pass to Santa Fe.

Though the shorter Jornada Route, also called the Cimarron Cutoff, provided less water, it saved the travelers ten days by cutting southwest across the Cimarron Desert to Santa Fe. The Cimarron Desert route was shorter and easier for the wagon parties than the mountainous Raton Pass, but travelers risked attacks by Native Americans in addition to shortages of water. Despite the hazards, the shorter route would end up carrying 75% of the Santa Fe Trail pioneers.

In 1825, the United States obtained a right of way from the Osage Indians, which officially established the Santa Fe Trail as a national "highway.”  In 1827, Independence, Missouri was founded and within a few years became the major outfitting point on the eastern end of the trail.

In 1834, Bent's Fort, a fur trade post on the upper Arkansas established was established near what is present-day La Junta, Colorado. A Bent, St. Vrain and Company party and wagons eastbound from Santa Fe, New Mexico in the late summer traveled by way of Taos and Raton Pass to Bent's Fort; then came down the Arkansas River to the Santa Fe Trail, opening the Bent's Fort branch of the Santa Fe Trail.