A study to quantify the toxicity and ecotoxicological pressure of pesticides in the Sancti Spíritus province, Cuba, was carried out between 2011 and 2014. A longitudinal descriptive work was designed for the study period to identify potential risks to the environment and also to human health associated with the use of pesticides in the country. The Spread Equivalents (ƩSeq) and Pesticide Occupational and Environmental Risk (POCER) indicators, as well as the Toxic Load (TL) methodology of Instituto Cubano de Sanidad Vegetal, were used to determine the toxicity and ecotoxicity of pesticide use. One hundred and twenty-four active ingredients corresponding to 62 chemical families were applied in the province during the study period. Organophosphates, triazoles, sulfonylurea, pyrethroids, inorganic compounds (such as copper), carbamates, dithiocarbamates, neonicotinoids, aryloxyphenoxypropionates, and organochlorines predominated due to their use frequency. The use of toxic pesticides, and the lack of personal protection equipment, among others, made workers, residents, and applicators the toxicological modules with the highest risk of exposure. On the other hand, aquatic organisms, and the persistence of the pesticides in the soil and in groundwater, are the modules with the highest ecotoxicological pressure. By using the POCER and ƩSeq indicators, a more accurate toxicity and ecotoxicity assessment for certain pesticides can be performed in Cuba, in comparison to the one obtained when using only the TL equation currently employed in the country. In addition, substituting the most toxic pesticides (e.g., parathion, endosulfan, bifenthrin, copper oxychloride, mancozeb, paraquat, diquat, and ametryn) with less toxic ones (e.g., cypermethrin, tebuconazole, triadimenol, and bispyribac-sodium) could help reduce synthetic pesticide pressure on humans and the environment.