Neurodegenerative diseases represent a major global health challenge, with cannabinoid receptor type 2 (CB2) emerging as a promising therapeutic target for its role in inflammation modulation and neuroprotection. Sesquiterpene lactone is a class of natural compounds with diverse molecular structures and known biological activities. This study aimed to explore sesquiterpene lactones for their potential as CB2 modulators using computational approaches such as molecular docking, molecular dynamics simulations (MDS), and ADMET predictions, to identify the promising candidates for neurodegenerative disease prophylactics. Out of 85 sesquiterpene lactones evaluated, podachaenin (PubChem CID: 15,828,229) exhibited the highest binding affinity to CB2 (- 12.242 kcal/mol), outperforming that of the native ligand (- 12.168 kcal/mol) and reference drugs apomorphine (- 9.482 kcal/mol), dantrolene (- 8.861 kcal/mol), and galantamine (- 9.689 kcal/mol). Hydrogen bonds as well as alkyl, Pi-alkyl, and van der Waal's interactions were present in the CB2-podachaenin complex providing structural intactness. MDS of 500 ns evaluated the stability of the protein-ligand complex and receptor structure in apo form through geometrical parameters: root mean square deviation, root mean square fluctuation, radius of gyration, solvent accessible surface area, and hydrogen bond length. Additionally, the binding free energy change calculation supplemented the initial inferences in terms of thermodynamic stability with a value of - 40.92 ± 4.56 kcal/mol. ADMET profiling also indicated favorable pharmacokinetic and pharmacodynamic properties, similar to that of the reference drugs. The preliminary results identified podachaenin as a possible CB2 modulator for treating neurodegenerative diseases and could be a hit compound in neuro-drug design. Further in vivo and in vitro studies are suggested to validate it as a hit candidate.