Xylia xylocarpa (Roxb.) Taub. is traditionally used to treat several diseases, including leprosy, wound healing, gonorrhea, rheumatism, anemia, diarrhea and ulcer. This study evaluated the anti-inflammatory and anti-nociceptive activities of methanolic extract of Xylia xylocarpa leaves (MEXX) via in vitro, in vivo as well as in silico models. In vitro anti-inflammatory activity was determined by human red blood cell membrane stabilization study and protein denaturation while in vivo anti-nociceptive activity was examined by the acetic acid-induced writhing test (AAWT) and formalin-induced paw licking test (FIPLT). Additionally, trans-5-hydroxypipecolic acid was an identified compound of MEXX which was subjected to molecular docking analysis followed by ADME/T and toxicity analysis. Qualitative phytochemical screening revealed that MEXX was enriched with carbohydrates, flavonoids, alkaloids, proteins, tannins and showed significant total phenolic (1222.66 ± 0.66 mg GAE/g dried extract) and flavonoids contents (325.33 ± 1.76 mg QE/g dried extract) in quantitative phytochemical screening. Inflammatory studies unveiled that; MEXX significantly (p < 0.05) inhibited the hemolysis of membrane and protein at different concentrations (31.25 - 1000 μg/mL). The extract also displayed statistically significant analgesic responses in the acetic acid and formalin-induced test at several doses (200 and 400 mg/kg b.w). In AAWT, the extract exhibited 13.67 and 51.37 % inhibition of writhing at the doses 200 and 400 mg/kg body weight respectively. In formalin-induced paw licking test, the early phase pain inhibition was 54.64 % at the concentration of 400 mg/kg while during the latter phase at 400 mg/kg, the inhibition of pain was 43.82 %.  According to molecular docking analysis, trans-5-hydroxypipecolic acid demonstrated a promising docking score against PDE4, COX-1, and COX-2 along with satisfied pharmacokinetic and toxicological properties. Finally, from the results it could be concluded that MEXX has potential anti-inflammatory and an-nociceptive effects that should require further investigation. HIGHLIGHTS Xylia xylocarpa minimizes the inflamation and pain Xylia xylocarpa showed significant analgesic activity Xylia xylocarpa revealed polyphenolic compounds including phenol, and flavonoid In in silico, trans-5-hydroxypipecolic acid possessed significant analgesic activity against COX-1 and COX-2 GRAPHICAL ABSTRACT