Paenibacillus polymyxa Prazmowski (= Bacillus polymyxa) is a Gram-positive, rod shaped, endospore-forming, widely distributed nonpathogenic bacterium with peritrichous flagella. It lives in the rhizosphere and inside plants (i.e., endophytic lifestyle), rarely in marine sediments or fermented foods, and is frequently used against plant, human, and animal pathogens. Due to their ability to survive extreme conditions, including high temperature, biocides, pressure, and UV exposure, endospores can tolerate pasteurization and persist in industrial equipment. P. polymyxa produces a variety of antimicrobial compounds (i.e., secondary metabolites)including lipopeptide polymyxin, fusaricidins, paenilipoheptin, paenilan, and tridecaptinthat are potentially useful for treating multidrug-resistant infections and other plant and human microbial pathogens. These combined features make it a model organism for sustainable plant, human, and animal health management within the One Health framework. The bacterium is easily culturable on agar-based media, can be genetically modified, and its whole-genome sequence is available. Recent studies have shown that the use of-omics technologies can increase the application of this bacterium in agriculture and industry for mitigating interkingdom diseases. This article discusses current knowledge of P. polymyxa, including its biocontrol potential in plant, human, and animal disease management, genome analysis, antibiotic production, and plant growthpromoting activities.