The increasing off-label use of medications needs a robust pharmacovigilance system. This is particularly crucial given the abundance of scientific data that can be harnessed to ensure a product's safety. Our review focuses on the off-label use of local anesthetics, a common practice in topical and intracameral applications. However, the occurrence of mydriasis, as indicated in the monographs/summaries of product characteristics, is an unexpected adverse event. Our aim is to provide a comprehensive understanding of mydriasis caused by local anesthetics, both as an unexpected adverse event and as an off-label use, to reinforce the importance of pharmacovigilance practices. We conducted a comprehensive search in Medline/PubMed and Google Scholar from two distinct perspectives: examining the occurrence of mydriasis with the use of local anesthetic as an adverse event and as an off-label use. Our search yielded 14 articles that reported mydriasis as an unexpected adverse event with the use of anesthetics, with dental procedures being a significant contributor to this type of event. Also, we identified eight articles that explored the off-label use of local anesthetics to induce mydriasis, with the most common method of drug administration being intracameral injection. These findings underscore the importance of our research in understanding the unexpected adverse event of mydriasis and the potential for off-label use of local anesthetics. They also highlight the need for continued involvement and vigilance in this area, as our understanding of these phenomena continues to evolve and further investigation is crucial. The use of local anesthetics for mydriasis holds significant promise, particularly in ophthalmological surgeries. This approach could potentially mitigate the adverse events associated with conventional mydriatics, offering a more efficient and safer alternative. Furthermore, using a single medication for akinesia, anesthesia, and mydriasis could significantly enhance the efficiency and convenience of surgical procedures. On the other hand, it is crucial to extend the knowledge of the mydriasis-anesthesia association through risk minimization activities (e.g., the inclusion of monographs/summary of product characteristics) to communicate the risk of mydriasis with the use of local anesthetics.