This study aimed to explore the efficacy of a multimodal analgesic regimen during the perioperative period for male patients undergoing knee replacement surgery. A total of 80 male patients scheduled for elective knee replacement surgery in our hospital's orthopedic department from March 2022 to March 2023 were selected through digital randomization. They were equally divided into a control group (received a conventional analgesic protocol) and an observation group (treated with a multimodal analgesic protocol that included patient-controlled analgesia (PCA), ultrasound-guided nerve block and physical analgesia). Parameters such as postoperative celecoxib capsule dosage, Visual Analog Scale (VAS) scores at 6, 12, 24 and 72 hours after surgery, levels of neurotransmitters and stress markers at the time of surgery, 24 hours postsurgery, and 72 hours post-surgery, sleep quality scores, the timing of first ambulation, and the overall incidence of adverse reactions were compared between the groups. After intervention, the observation group showed a statistically significant reduction in the dosage of celecoxib capsules compared to the control group (p < 0.05). VAS scores in the observation group were significantly lower than those in the control group at all measured time points. Furthermore, levels of substance P (SP), beta-endorphin (β-EP), 5-hydroxytryptamine (5-HT), cortisol (Cor), C-reactive protein (CRP) and white blood cell (WBC) counts in the observation group were significantly lower than those in the control group at 24-and 72-hours post-surgery. The incidence of adverse reactions was also significantly lower in the observation group (p < 0.05). We conclude that implementing a multimodal analgesic protocol in the perioperative period could significantly reduce pain, regulate neurotransmitter and stress levels, and enhance sleep quality in the early postoperative phase of male patients undergoing knee replacement surgery.