Background: This study was conducted to evaluate the analgesic activity of different extracts of Lippia alba (L. alba) along with in silico evaluation of analgesic activity of the isolated compounds from L. alba against cyclooxygenase-2 enzyme and ADME/T analysis of isolated compounds. Method: In vivo analgesic activity of different extracts of L. alba was evaluated by acetic acid-induced writhing, tail immersion and hot plate on Swiss albino mice of either sex. In silico activity of the isolated compounds and ADME/T analysis were performed by Schrödinger-Maestro (Version 10.1) and OSIRIS Data warrior (version 4.6.1) softwares. Results: Three different extracts (Methanolic extract: ME; Petroleum ether extract: PEE; Dichloromethane extract: DCME) of 250 mg/kg and 500 mg/kg doses were used in the experiments to evaluate analgesic activity. In acetic acid-induced writhing test, significant results were seen for PEE (500 mg/kg) and DCME (500 mg/kg), which were 53.09 ± 2.87 & 50.09 ± 4.24%, respectively. In tail immersion test, the best latency time was found at + 60 min for PEE (500 mg/kg) which is (5.65 ± 0.25) sec. For hot plate test, DCME at a dose 500 mg/kg showed the highest increase in latency time, which was 13.48 ± 0.33 s. In the case of in silico evaluation of analgesic activity, the compounds such as geranial, neral, (E)caryophyllene, caryophyllene oxide, mussaenide, and 8-epi-loganin meet the condition of Lipinski's rule of five. Among these safe compounds, 8-epi-loganin showed the best docking score of − 8.17 kcal/mol against cyclooxygenase-2 enzyme (PDB ID: 6COX), which was almost similar to that of the standard drug, Celecoxib (− 11.11 kcal/mol). Conclusion: In conclusion, L. alba can be a potent source of analgesic medicine and further modification and simulation studies are required to establish the effectiveness of 8-epi-loganin.