The desiccation of wetlands is a process associated with the dynamics of urban growth and expansion of the agricultural frontier. This article aims to evaluate the influence of the desiccation of the Ciénaga de Aguablanca on regional climate. The periodization of the desiccation and urban growth of Cali was reconstructed under the theoretical contributions of environmental history. As complementary sources, maps, aerial photographs, and diagrams of the city were obtained from 1944 to 2020, with which the hydromorphological changes in the Ciénaga de Aguablanca were represented. Data from six hydroclimatological stations were statistically analyzed with Pettitt’s test, trend analysis, and Rclimdex. The results indicate a reduction of 99% in the area of the wetlands, from 19.2 km 2 in 1944 to 0.2 km 2 by 2020. Additionally, a break point was observed in 1970, preceded by the process of wetland desiccation and waterproofing of the eastern part of Cali, along with significant differences between temperature series inside and outside the urban perimeter. Another break point was detected in 1985 in the flow series, associated with the construction of the La Salvajina dam. Monthly rainfall showed a tendency to increase, but its temporal distribution was uneven, given that rainfall volume showed a tendency to increase over short times. Regional climate changes can occur at a much faster rate than global variations due to the anthropogenic actions of wetland intervention.