The development of antibiotic agents has revolutionized the treatment of infectious diseases and clinical practice. However, antibiotic overuse, together with biologic evolution, has resulted in escalating antibiotic resistance of bacteria; with the One Health concept, it affects our planet including animals, aquatic wildlife, rivers, groundwater, lakes, sea water, aqua farming, and soil. This situation threatens our ability to treat infections effectively in the near future and raises the alarming question of whether we are getting close to the post-antibiotic era. Several measures are suggested to prevent the apocalyptic consequence of antibiotic overuse, few of which are novel with thinking outside the box.