Growing evidence indicates that paternal condition significantly influences pregnancy outcomes and offspring health. However, assessing the safety of paternal drug exposure via randomized controlled trials poses ethical challenges, and relevant clinical studies consume a lot of resources to evaluate only a few drugs. Currently, safety data on paternal drug exposure are scarce. To investigate the impact of paternal drug exposure on fertility, pregnancy outcomes, and offspring health. Data from the FDA adverse event reporting system (FAERS) were analyzed (2010-2022). Disproportionality analyses were used to identify signals of each drug-adverse event pair associated with paternal drug exposure in a different hierarchical manner. Out of the 16,180,533 reports, 3210 were related to paternal exposure, encompassing 7808 concomitant adverse events. Drugs used to treat rheumatoid arthritis, cancer, and infections were primary sources of paternal exposure. Analysis identified 115 signals concerning reproductive health. Notably, the signals of diazepam-small for dates baby and finasteride-cryptorchidism were particularly significant (reporting odds ratio, ROR>800, N>10). Moreover, spontaneous abortion signals occur frequently in biologics for the treatment of immune inflammation; the use of immunosuppressive drugs was associated with the highest number of congenital anomalies, with the strongest signals for belatacept-skeletal dysplasia, and tacrolimus-talipes. Only mycophenolic acid, estrogen and imatinib have signals on male fertility. Anti-tumor agents had high numbers of each reproductive toxicity, with the highest values of trisomy 13 signals associated with etoposide and cisplatin. This is the first research to fully assess the safety of paternal exposure to the majority of medications in terms of reproduction. Clinical and scientific researchers should pay close attention to the list of risk medications included in this study, particularly the following association combinations: biologics used to treat inflammatory diseases-abortion, diazepam-small for date baby, finasteride-cryptorchidism, etoposide and cisplatin-13 trisomy.