Objective: To evaluate the safety and efficacy of antidepressants and antiepileptic drugs in the treatment of neuropathic pain. Methods: Cochrane library, PubMed, Embase, CNKI, Wanfang, and other databases were searched using RevMan 5.3 software for data analysis to collect randomized controlled studies comparing antiepileptics and antidepressants for neuropathic pain. Results: This study enrolled a total of 1073 participants in 16 randomized controlled trials. Antiepileptic drugs and antidepressants ought to improve neuropathic pain patients’ treatment scores [OR=1.10, 95% CI(0.64 to 1.89), P =0.74], pain relief rate [OR=1.10, 95% CI(0.64 to 1.89), P =0.74], and incidence of adverse reactions [OR=0.94, 95% CI(0.48 to 1.85), P =0.87] without showing a statistically significant difference; The results of the single-agent study revealed that only pregabalin, as opposed to venlafaxine, had a significant effect on pain scores; the subgroup analysis revealed that publication bias had no effect on the study’s findings. The heterogeneity may stem primarily from different follow-up durations and drug types. Conclusion: There is no clear distinction between adverse effects and effectiveness.