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Background: Brucellosis is a zoonotic disease and prevalent in livestock animals. The bacteria reside inside the macrophage cells of host. The WHO endorsed the combination treatment therapy for brucellosis as compared to monotherapy to avoid relapse and resistance. Therefore, we developed nanoparticles incorporating doxycycline and rifampicin in combination. Objective: The aim of the study is to develop polymeric nanoparticles incorporating doxycycline as well as rifampicin and investigate the antibacterial activity of nanoparticles in U937 human macrophage cells infected with B. abortus. Methods: Polymeric nanoparticles were developed by emulsion-solvent diffusion method and characterization was done. Results: The nanoparticles with high entrapment efficiency of both drugs were developed successfully. Scanning electron microscopy revealed spherical morphology with a size ranging ~450nm, which can be easily engulfed by macrophages. Zeta potential confirmed colloidal stability. Differential scanning calorimetry and X-ray diffraction suggested amorphization of doxycycline and rifampicin in nanoparticles. Fourier transfer infrared spectroscopy could not confirm interaction of drugs with AOT. In vitro haemolysis study confirmed safety of nanoparticles (<10%) for IV administration. Further, nanoparticles revealed the sustained release of both drugs, which followed diffusion kinetics. Nanoparticles were found stable for 6 months as per WHO guidelines. The internalization study revealed nanoparticles can be easily uptake by U-937 human macrophage cells. The efficacy study demonstrated significantly high antibacterial activity of nanoparticles as compared to free drug solution in U937 human macrophage cells infected with Brucella abortus. Conclusion: It can be concluded that developed nanoparticles entrapping doxycycline and rifampicin combination could be considered as a promising delivery system for enhancing the antibacterial activity against Brucella abortus.