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Abstract Background Isoxazole is an important pharmacophore in medicinal chemistry with a wide range of pharmacological activities. The present study deals with the synthesis and evaluation of antinociceptive potential of nine novel 3-substituted-isoxazole-4-carboxamide derivatives. Synthesis In the first step, respective oxime was prepared and further treated with ethylacetoacetate and anhydrous zinc chloride followed by hydrolysis of ester to furnish 3-substituted isoxazole-4-carboxylic acid. The respective carboxylic acids were converted to acid chlorides and condensed with aromatic amines to get the target carboxamide derivatives (A1–A5 and B1–B5). These compounds were characterized by FTIR, 1HNMR, 13CNMR and elemental analysis data and screened for their analgesic activity using acetic acid-induced writhing assay and hot plat test in mice and compared with the standard centrally acting analgesic, tramadol. Results All the synthesized carboxamide derivatives showed low to moderate analgesic activity. Among the synthesized derivatives B2 having methoxy (OCH3) showed high analgesic activity as compared to tramadol both in acetic acid-induced writhing assay and hot plate assay at dose of 6 mg/kg. To examine the involvement of opioidergic mechanism in the mediation of analgesic effects of isoxazole derivatives animals were further treated with non-selective opioid analgesic, naloxone (0.5 mg/kg). The results showed that compounds A3 and B2 follow a non-opioid receptor pathway in the mediation of analgesic effects. Synthesized compounds A3 and B2 were docked against non-opioid receptors COX-1 (3N8X), COX-2 (1PXX) and human capsaicin receptor (HCR, 3J9J) to analyze their binding interactions. They showed binding energies in the range of − 7.5 to − 9.7 kcal/mol. Conclusions The results indicated that isoxazole carboxamide derivatives possess moderate analgesic potential especially compounds A3 and B2 can be considered as lead molecules and explored further for pain management with fewer side effects.