Central nervous system tuberculosis (CNS-TB) is the most severe extra-pulmonary manifestation of tuberculosis (TB), facing significant challenges due to the limited penetration of anti-TB drugs (ATDs) across the blood-brain barrier (BBB) and their insufficient concentrations at the site of infection. This study aimed to enhance the efficacy of ATDs by encapsulating them in methyl-β-cyclodextrin (M-β-CD) microparticles (ATD-MP) using spray drying, intended for intranasal delivery to manage CNS-TB. M-β-CD microparticles loaded with isoniazid (INH) and rifampicin (RIF) exhibited spherical shapes with slightly deflated surfaces and particle sizes of 6.24 ± 0.77 μm and 5.97 ± 0.50 μm, respectively. M-β-CD improved the permeation of ATDs through RPMI-2650 cell monolayers while reducing drug cytotoxicity. Pharmacokinetic and biodistribution analysis demonstrated that intranasal administration of ATD-MP significantly enhanced the trans-nasal brain delivery of ATDs and their distribution in the brain, achieving the minimum inhibitory concentration. In a murine model of CNS-TB, intranasal insufflation of ATD-MP for four weeks led to a significant reduction (∼0.78 Log10 CFU) in mycobacterial burden in the brain compared to the untreated group (∼3.60 Log10 CFU). These preclinical results underscore the potential of intranasal administration of M-β-CD microparticles as an effective therapeutic strategy for combating brain inflammation in CNS-TB.