Objective: To study the efficacy of naloxone combined with omeprazole in the treatment of acute alcoholism and its effect on serum inflammatory factor levels. Methods: 68 patients with acute alcohol poisoning from January 2021 to May 2025 were selected and randomly divided into a control group (34 cases) and an observation group (34 cases). The control group was given conventional treatment, and the observation group was treated with naloxone and omeprazole in addition to conventional treatment. The treatment effect was evaluated by comparing the recovery status, changes in inflammatory factor levels and cognitive function scores between the two groups of patients after treatment. Results: After treatment, the time for symptom relief in the excitement phase and ataxia phase of the observation group (37.87 ± 4.93 minutes vs. 42.28 ± 5.18 minutes) was significantly shorter than that of the control group (p = 0.030), and the time for symptom relief in the coma phase (68.72 ± 15.34 minutes vs. 89.85 ± 18.86 minutes) was also significantly shorter than that of the control group (p < 0.001). The time to fully wake up in the observation group (4.01 ± 1.05 hours vs. 5.16 ± 1.24 hours) was significantly shorter than that in the control group p = 0.010), and the time to fully wake up in the coma period (4.22 ± 2.15 hours vs. 9.80 ± 3.42 hours) was also significantly shorter than that in the control group (p < 0.001). The MMSE score showed that the cognitive function of the observation group improved more significantly after treatment (27.90 ± 3.34 points vs. 25.24 ± 4.62 points). The cognitive score of the control group also improved after treatment, but the difference was not as significant as that of the observation group (p = 0.040). Conclusion: Naloxone combined with omeprazole can effectively shorten the symptom relief time, improve cognitive function, and significantly reduce serum inflammatory factor levels in patients with acute alcoholism. It has good clinical efficacy and is worthy of promotion and application in the treatment of acute alcoholism.