Mycobacterium tuberculosis (M.tb) remains a formidable global health threat. The increasing drug resistance among M.tb clinical isolates is exacerbating the current tuberculosis (TB) burden. In this study we focused on identifying novel repurposed drugs that could be further investigated as potential anti-TB drugs. We utilized M.tb RNA methyltransferase Rv3366 (spoU) as a potential drug target due to its imperative activity in RNA modification and no structural homology with human proteins. Using computational modeling approaches the structure of Rv3366 was determined followed by high throughput virtual screening of Food and Drug Administration (FDA) approved drugs to screen potential binders of Rv3366. Molecular dynamics (MD) simulations were performed to assess the drug-protein binding interactions, complex stability and rigidity. Through this multi-step structure-based drug repurposing workflow two promising inhibitors of Rv3366 were identified, namely, Levodopa and Droxidopa. This study highlights the significance of targeting M.tb RNA methyltransferases to combat drug-resistant M.tb. and proposes Levodopa and Droxidopa as promising inhibitors of Rv3366 for future pre-clinical investigations.