Retrospective assessment of agricultural workers’ pesticide exposure is essential for understanding and establishing links between their occupational activities throughout their careers and the onset of potential diseases such as cancer or neurodegenerative disorders. Reliable data, generated through a precise and structured method for documenting occupational exposure histories, are scarce. Sugarcane, the most widespread agricultural crop in Réunion, involves the use of numerous plant protection products (PPPs) to which agricultural workers are exposed. No previous study has identified the number of these workers, the PPPs to which they are and/or have been exposed over time, or the potential health effects that may result from this exposure. We used three databases, two of which were developed by Santé publique France, to answer the following questions: Which PPPs have been applied to sugarcane over the past few decades on the island of Réunion? What are their health effects? And what are the characteristics of the affected agricultural worker population? The first database is a crop-exposure matrix (CEM) specific to sugarcane cultivation on Réunion, through which we identified all PPPs used on this crop since the 1960s, as well as the frequency and probability of their use. The second data source is the CipaTox database; it was established to document the health effects of all active ingredients (AI) in PPPs registered in France since 1961, with a focus on carcinogenicity, mutagenicity, and reproductive toxicity (CMR) as well as endocrine disruption (ED). Finally, the third source consists of the agricultural censuses (RA) from 1981, 1989, 2000, and 2010, which made it possible to identify the sociodemographic characteristics of sugarcane workers in Réunion. By cross-referencing these three data sources, we calculated the prevalence of occupational exposure over the four years covered by the RA to PPPs used on sugarcane in Réunion and identified the health effects they may cause. Our study shows that in 1981, 1989, 2000, and 2010, 25 different active ingredients were used on sugarcane, including 19 herbicides, 3 insecticides, 2 rodenticides, and 1 fungicide. The main compounds are 2,4-D, ametryn, atrazine, Beauvaria tenella 96, chlorpyrifos-ethyl, diuron, and glyphosate. Between 44% (1981) and 88% (2010) of sugarcane workers in Réunion—whose numbers fell from 16,777 (1981) to 7,194 (2010)—were exposed to at least one substance toxic to human health and classified as CMR or PE. This research helps guide prevention efforts for agricultural workers by identifying pesticides that may have adverse effects on their health. It encourages the implementation of several measures, including raising awareness among agricultural workers about the chemical risks associated with pesticide use, promoting alternative methods of sugarcane production, limiting the use of PPPs, restricting the use of PPPs containing active ingredients classified as CMR or PE, wearing personal protective equipment appropriate for the region’s climatic conditions, and finally, providing information and training to general practitioners and occupational health physicians to facilitate the recognition of occupational diseases.