Effective pain relief in rodent models , with reduced drug doses , represents an important objective in preclinical pharmacology .This study aimed to evaluate the analgesic effect of nefopam and medetomidine at graded doses, and to assess the synergistic antinociceptive interaction when combined at sub-analgesic levels. Swiss albino mice were subjected to the hot plate test (55.0 ± 0.1°C) as a model of acute thermal pain. The ED₅₀ for both drugs was determined using the up-and-down method. Nefopam was administered intraperitoneal at doses of 3, 6, and 12 mg/kg, while medetomidine was given at 50, 100, and 200 µg/kg. Latency time and % maximal possible effect (%MPE) were recorded at multiple time points post-injection. The highest dose of medetomidine (200 µg/kg) produced a peak latency of 17.60 ± 0.03 sec with %MPE over 90% at 30 minutes, while the 12 mg/kg dose of nefopam showed latency of 12.50 ± 0.56 sec and %MPE above 80%, both with significant differences compared to lower doses and control (p<0.001). In the third experiment, sub-analgesic doses of nefopam (3 mg/kg) and medetomidine (45 µg/kg), ineffective when given alone, produced a full analgesic response when administered together, with latency of 11.50 ± 0.92 sec and %MPE reaching 100% at 30 minutes (p<0.001). The results indicate a clear dose- and time-dependent analgesic effect for both drugs and demonstrate a synergistic interaction at low doses, which may support their combined use for pain control with minimized side effects in laboratory or clinical veterinary settings.