Background: Cassava mosaic disease (CMD), caused by the Sri Lankan cassava mosaic virus (SLCMV), significantly increases cassava yield losses in Thailand, with losses ranging from 30% to 80%, and is exacerbated by limited access to healthy planting materials. Methods: This study explored salicylic acid (SA) as a potential treatment for enhancing disease resistance in CMD infected cassava plants. SA was applied at 100 and 200 mg/mL, and its effects were evaluated using quantitative real-time polymerase chain reaction (qPCR) and reverse transcription qPCR (RT-qPCR) to measure viral loads and the expression levels of resistance genes. Results: Although SA treatment did not considerably affect disease severity, foliar CMD symptoms visibly decreased, particularly with 200 mg/mL SA, which also reduced SLCMV particle counts at 1- and 2-weeks post-treatment. SA upregulated the expression of pathogenesis-related proteins (PRs), including HSP90.9, WRKY59, SRS1, and PR9e. Additionally, SA enhanced the regulation of secondary metabolite pathways involving L-serine within the glycine, serine, and threonine metabolism, as well as the phenylpropanoid biosynthesis pathways. Conclusions: These findings collectively indicate that SA enhances resistance through the systemic acquired resistance (SAR) pathway and can serve as a potential strategy for the management of CMD, particularly in regions where healthy cassava planting materials are scarce. The study highlights the efficacy of SA in reducing viral particles, inducing the immune response, and providing a promising approach for controlling CMD.