This study aimed to analyse how socio-environmental conditions affected the early evolution of COVID-19 in 14 urban sites in South America based on a spatio-temporal multidisciplinary approach. The daily incidence rate of new COVID-19 cases with symptoms as the dependent variable and meteorological-climatic data (mean, maximum, and minimum temperature, precipitation, and relative humidity) as the independent variables were analysed. The study period was from March to November of 2020. We inquired associations of these variables with COVID-19 data using Spearman's non-parametric correlation test, and a principal component analysis considering socio economic and demographic variables, new cases, and rates of COVID-19 new cases. Finally, an analysis using non-metric multidimensional scale ordering by the Bray-Curtis similarity matrix of meteorological data, socio economic and demographic variables, and COVID-19 was performed. Our findings revealed that the average, maximum, and minimum temperatures and relative humidity were significantly associated with rates of COVID-19 new cases in most of the sites, while precipitation was significantly associated only in four sites. Additionally, demographic variables such as the number of inhabitants, the percentage of the population aged 60 years and above, the masculinity index, and the GINI index showed a significant correlation with COVID-19 cases. Due to the rapid evolution of the COVID-19 pandemic, these findings provide strong evidence that biomedical, social, and physical sciences should join forces in truly multidisciplinary research that is critically needed in the current state of our region.