Osteoarthritis (OA) of the hip and knee is a common age-related degenerative disease characterized by joint pain, stiffness, and gait disturbances. This study investigated the influence of genetic polymorphisms in the (rs1799971) and (rs4633, rs4680, rs4818, and rs6269) genes on the postoperative analgesic requirements in 195 diabetic and non-diabetic patients undergoing total hip or knee arthroplasty. The prospective study included all patients who were admitted between January and September 2020 and agreed to participate. Postoperative pain management was assessed based on acetaminophen, ketoprofen, and morphine consumption on the first and second postoperative day. Multilevel regression analyses revealed a significant three-way interaction between diabetes, type of analgesic, and rs1799971 polymorphism, indicating different analgesic dosing patterns in diabetic and non-diabetic patients. Two-way interactions between diabetes and polymorphisms rs4633, rs4680, and rs6269 further influenced the analgesic requirements. No significant associations were found for rs4818. The results show that diabetes and genetic factors significantly influence opioid requirements and pain perception. Given the complexity of pain management in diabetic patients, personalized analgesic strategies tailored to genetic and metabolic profiles could be useful in postoperative pain management and reducing opioid consumption.