Objective To observe the clinical efficacy and safety of botulinum toxin type A (BTX-A) combined with compound betamethasone local injection in the treatment of post-herpetic neuralgia (PHN), to provide reference for clinical practice. Methods 150 PHN patients admitted in Zhongshan Second People’s Hospital from March 2021 to November 2022 were selected as the research objects, and they were divided into A, B, C group by random number table method, 50 patients in each group. Patients in group A received local injection of BTX-A, patients in group B received compound betamethasone combined with lidocaine intervention, and patients in group C received compound betamethasone combined with lidocaine and BTX-A intervention. The treatment efficacy, dermatology life quality index (DLQI) score, the serum β-endorphin (β-EP), serum substance P (SP) and the occurrence of adverse reactions were compared among the three groups. Results The overall efficacy of patients in group C was better than that in group A and group B (P<0.05). There was no significant difference in overall efficacy between group A and group B (P>0.05). There was no significant difference in the total effective rate between the three groups (P>0.05). Patients in three groups had lower DLQI score at 4 weeks and 12 weeks after treatment than before treatment, and the DLQI score in group C at 4 weeks and 12 weeks after treatment was lower than that in group A and group B (P<0.05). Patients in three groups had higher β-EP levels at 4 weeks and 12 weeks after treatment than before treatment, SP levels were lower than before treatment, and the β-EP level in group C at 4 weeks and 12 weeks after treatment was higher than that in group A and group B, and the SP level was lower than that in group A and group B (P<0.05). There was no significant difference in the incidence of adverse reactions among the three groups (P>0.05). Conclusion The combination of compound betamethasone, lidocaine and BTX-A are used in patients of PHN, which has significant efficacy, can relieve pain and improve quality of life, and it has good safety.