INTRODUCTION: This study aimed to compare the effects of pregabalin, gabapentin, and duloxetine on diabetic peripheral neuropathy (DPN) to guide tailored treatment. MATERIALS AND METHODS: In this retrospective study, 180 patients with type 2 diabetes and DPN were matched 1:1:1 across three groups based on HbA1c and age, resulting in 60 patients per group. Clinical data were collected, and the painDETECT score was used to evaluate treatment response over six weeks. RESULTS: After six weeks, the gabapentin group had significantly higher pain scores than the pregabalin (P = 0.002) and duloxetine groups (P <
0.001). The pregabalin group's scores were higher than the duloxetine group's, but not significantly (P = 0.62). Side effects were more frequent with duloxetine (23.3 %) compared to gabapentin (1.7 %) and pregabalin (6.7 %) (P = 0.001). Among those with over 50 % improvement, mean HbA1c levels were 9.42 for gabapentin, 10.43 for pregabalin, and 7.72 for duloxetine. Duloxetine significantly lowered HbA1c compared to gabapentin (P = 0.001) and pregabalin (P = 0.001), with no significant difference between gabapentin and pregabalin (P = 0.45). CONCLUSION: Duloxetine and pregabalin effectively treat DPN. Gabapentin and pregabalin are suitable for patients with HbA1c over 8.7, while duloxetine is better for those with well-controlled HbA1c. Treatment should consider side effects, adherence, costs, and response time. LEVEL OF THE EVIDENCE: Level III retrospective cohort study.