The present study was designed to investigate the antinociceptive effects of methanolic leaf extract of Swietenia mahagoni (MESM) on acrylamide-induced painful neuropathy in rats. The intraperitoneal administration of acrylamide (30 mg/kg; for 24 consecutive days) has been employed for the induction of painful neuropathy. Acrylamide induced nociceptive pain sensitive changes, which have been assessed by hot plate, Von Frey Hair, and tail immersion tests at different time intervals, that is, 0, 6, 12, 18, and 24th day. Furthermore, the biochemical changes, that is, thiobarbituric acid-reactive substances, reduced glutathione, and total calcium levels have been estimated in sciatic nerve tissue on 24th day and histopathological changes have been observed in sciatic nerve tissue sample. MESM and pregabalin have been administered for 14 consecutive days before 1 h of the each acrylamide injection. Administration of acrylamide resulted in significant changes in behavioral and biochemical parameters. Pretreatment of MESM ameliorated acrylamide-induced behavioral, biochemical, and histopathological changes in a dose-dependent manner, which is similar to that of pregabalin-pretreated group. These findings suggested that the neuroprotective effect of S. mahagoni may be due to its potential of antioxidative, calcium channel modulatory, and neuroprotective action.