Aim: First extensive reformulation of clofazimine (CLZ) in nanoporous silica particles (NSPs) for tackling antibiotic-resistant tuberculosis (TB) infections. Materials & methods: Solid-state characterization of several CLZ-encapsulated NSP formulations was followed by in vitro drug solubility, Caco-2 intestinal cells drug permeability and TB antibacterial activity. Results: NSPs stabilize the amorphous state of CLZ (shelf stability >6 months) and dramatically increase the drug solubility in simulated gastric fluid (up to 20-fold) with different dissolution kinetics depending on the NSPs used. CLZ encapsulation in NSP substantially enhances the permeation through model intestinal cell layer, achieving effective antimicrobial concentrations in TB-infected macrophages. Conclusion: Promising results toward refurbishment of an approved marketed drug for a different indication suitable for oral anti-TB formulation.