Antibiotic resistance is an increasing global problem for public health, and focusing on biofilms has provided further insights into resistance evolution in bacteria. Resistance is innate in many bacterial species, and many antibiotics are derived from natural molecules of soil microorganisms. Is it possible that nature can help control AMR diffusion? In this review, an analysis of resistance mechanisms is summarized, and an excursus of the different approaches to challenging resistance spread based on natural processes is presented as “lessons from Nature”. On the “host side”, immunotherapy strategies for bacterial infections have a long history before antibiotics, but continuous new inputs through biotechnology advances are enlarging their applications, efficacy, and safety. Antimicrobial peptides and monoclonal antibodies are considered for controlling antibiotic resistance. Understanding the biology of natural predators is providing new, effective, and safe ways to combat resistant bacteria. As natural enemies, bacteriophages were used to treat severe infections before the discovery of antibiotics, marginalized during the antibiotic era, and revitalized upon the diffusion of multi-resistance. Finally, sociopolitical aspects such as education, global action, and climate change are also considered as important tools for tackling antibiotic resistance from the One Health perspective.