RAB2B, a member of the Rab GTPase family involved in Golgi-endoplasmic reticulum vesicular trafficking, has been associated with chronic migraine through altered exosomal protein profiles. This study employs in silico approaches to investigate the evolutionary conservation of RAB2B and its potential interaction with common migraine therapeutics. Phylogenetic analysis of coding sequences from diverse mammalian species revealed exceptional conservation (bootstrap values 90-100%), supporting its essential cellular function. Molecular docking analysis against the RAB2B crystal structure (PDB: 2A5J) with three non-steroidal anti-inflammatory drugs (NSAIDs) showed differential binding affinities: naproxen (-4.37 kcal/mol) and mefenamic acid (-4.21 kcal/mol) exhibited stronger predicted binding than aspirin (-3.18 kcal/mol). These computational findings suggest that RAB2B’s structural pocket may differentially interact with migraine therapeutics, providing a preliminary computational framework for exploring the structural relevance of RAB2B in migraine-associated pathways.