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Although it has no known biochemical role in living organisms, bismuth has been used to treat syphilis, diarrhea, gastritis and colitis for almost a century due to its nontoxic nature to mammalian cells. When prepared via a top-down sonication route from a bulk sample, bismuth subcarbonate (BiO)₂CO₃ nanoparticles (NPs) with an average size of 5.35 ± 0.82 nm exhibit broad-spectrum potent antibacterial activity against both the gram-positive and gram-negative bacteria including methicillin-susceptible <i>Staphylococcus aureus</i> (DSSA), methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), drug-susceptible <i>Pseudomonas aeruginosa</i> (DSPA) and multidrug-resistant <i>Pseudomonas aeruginosa</i> (DRPA). Specifically, the minimum inhibitory concentrations (MICs) are 2.0 µg/mL against DSSA and MRSA and 0.75 µg/mL against DSPA and DRPA. In sharp contrast to ciprofloxacin, AgNPs and meropenem, (BiO)₂CO₃ NPs show no sign of developing Bi-resistant phenotypes after 30 consecutive passages. On the other hand, such NPs can readily overcome the resistance to ciprofloxacin, AgNPs and meropenem in DSPA. Finally, the combination of (BiO)₂CO₃ NPs and meropenem shows a synergistic effect with the fractional inhibitory concentration (FIC) index of 0.45.