After they moved the city was finally consolidated in 1622 and took its original name of Santa Cruz de la Sierra given by Ñuflo de Chaves over 60 years before.
Remnants of the original settlement can be visited in Santa Cruz la Vieja ("Old Santa Cruz"), an archaeological site south of San José de Iquitos.
Like in many parts of Spanish America at the time, angered by the reforms the criollos saw as a threat to their way of life, and taking advantage of the Peninsular War, the local population, led by Antonio Vicente Seonane, revolted on September 24, 1810, overthrowing the governor delegate.
A junta of local commanders took control of the government in his place.
Many of the inhabitants, however, chose to stay behind and continued living in the original location.
For much of its history, Santa Cruz was mostly a small outpost town, and even after Bolivia gained its independence in 1825 there was little attention from the authorities or the population in general to settle the region.Over the next 200 years, several tribes were either incorporated under Spanish control or defeated by force.The city also became an important staging point for Jesuit Missions to Chiquitos and Moxos, leading to the conversion of thousands of Guaranies, Moxeños, Chiquitanos, Guarayos and Chiriguanos that eventually became part of the racially mixed population of the modern Santa Cruz, Beni, Pando and Tarija departaments of Bolivia.Animosity towards imperial authorities began at the turn of the 18th century, when the new system of intendencias reached the new world.The seat of government was taken away from the city and moved to Cochabamba, and many of the powers delegated by the viceroyalty were now in the hands of appointees of the crown.