Rice cultivation in Northeast India (NEI) primarily relies on rainfed conditions, making it susceptible to severe drought spells that promote the onset of brown spot disease (BSD) caused by Bipolaris oryzae. This study investigates the response of prevalent rice cultivars of NEI to the combined stress of drought and B. oryzae infection. Morphological, physiological, biochemical, and molecular changes were recorded post-stress imposition. Qualitative assessment of reactive oxygen species through DAB (3,3-diaminobenzidine) assay confirmed the elicitation of plant defense responses. Based on drought scoring system and biochemical analyses, the cultivars were categorized into susceptible (Shasharang and Bahadur), moderately susceptible (Gitesh and Ranjit), and moderately tolerant (Kapilee and Mahsuri) groups. Antioxidant enzyme accumulation (catalase, guaiacol peroxidase) and osmolyte (proline) levels increased in all stressed plants, with drought-tolerant cultivars exhibiting higher enzyme activities, indicating stress mitigation efforts. Nevertheless, electrolyte leakage and lipid peroxidation rates increased in all stressed conditions, though variations were observed among stress types. Based on findings from a previous transcriptomic study, a total of nine genes were chosen for quantitative real-time PCR analysis. Among these, OsEBP89 appeared as a potential negative regulatory gene, demonstrating substantial upregulation in the susceptible cultivars at both 48 and 72 h post-treatment (hpt). This finding suggests that OsEBP89 may play a role in conferring drought-induced susceptibility to BSD in the rice cultivars being investigated. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-024-01447-4.