Despite the widespread use of omeprazole (OME), there are still concerns about its long-term safety and tolerability, especially with long-term or indiscriminate use. This study was designed to evaluate the effect of 90 days sub-chronic administration of OME on haematological, biochemical, antioxidant, reproductive and histopathological parameters in male and female rats. Forty-eight (48) Wistar rats of both sexes were divided into 4 groups of 6 male and 6 female animals each. Group I received 10 mL/kg normal saline, while Groups II – IV received 0.12 mg/kg, 0.57 mg/kg, 2.85 mg/kg of OME respectively for 90 days. At the end of 90 days, 5 mL blood sample was collected, and vital organs were harvested for relevant analyses. In this study, OME did not elicit any significant (P>0.05) change in the body weight or weight of vital organs, but elicited a significant (P<0.05) reduction in sperm count at the supratherapeutic dose (2.85 mg/kg). The supratherapeutic dose of OME produced significant increase in cholesterol (P<0.0001) and LDL (P<0.0001) in female rats. OME did not generally produce a significant change in haematological parameters. OME elicited a significant decrease in CAT (P<0.05) in female and combined animals. Additionally, histopathological presentations of vital organs were generally non-abnormal. From this study, it can be concluded that long term administration of OME is generally safe and tolerable, especially at lower doses. Findings from this study suggest that OME may potentially induce changes in sperm characteristics (in relation to male rats), hepatoxicity, hypercholesteremia, hyperlipidemia and thrombocytosis over a long duration, at higher doses and especially in female animals.