Objective: To investigate the clinical efficacy and safety of CT-guided ozone combined with sphenopalatine ganglion block in the treatment of atypical facial pain. Materials and Methods: 92 patients with atypical facial pain admitted to our department from February 2014 to October 2018 were retrospectively analyzed. They were divided into experimental group and control group according to the method of computer random number table, 46 in each group. All patients in the experimental group were treated with CT-guided transpterygopalatine fossa ozone combined with sphenopalatine ganglion block, while those in the control group received simple sphenopalatine ganglion block. Visual analogue scale (VAS) was used to evaluate the degree of pain, and Pittsburgh sleep quality index (PSQI) was used to evaluate the quality of sleep. The degree of pain and sleep quality before and after operation were compared between the two groups, and the related complications were recorded. RESULTS: Both groups of patients were followed up to 6 months. The VAS score of the experimental group was significantly lower than that of the control group (P < 0.05). Sleep therapy volume of the experimental group was significantly improved within 6 months after treatment, and PSQI score was significantly lower than that of the control group (P < 0.05). The main complications in the experimental group included short-term facial pain and discomfort, facial numbness, no bleeding, intracranial infection and other serious complications. Conclusion: CT-guided transpterygopalatine fossa ozone combined with sphenopalatine ganglion block is safe and effective in the treatment of atypical facial pain, which can effectively relieve pain and improve the quality of life of patients.