Lactobacillus johnsonii has been used as a probiotic for decades to treat a wide range of illnesses, and has been found to have specific advantages in the treatment of a number of ailments. We reviewed the potential therapeutic effects and mechanisms of L. johnsonii in various diseases based on PubMed and the Web of Science databases. We obtained the information of 149 L. johnsonii from NCBI (as of 14 February 2023), and reviewed their comprehensive metadata, including information about the plasmids they contain. This review provides a basic characterization of different L. johnsonii and some of their potential therapeutic properties for various ailments. Although the mechanisms are not fully understood yet, it is hoped that they may provide some evidence for future studies. Furthermore, the antibiotic resistance of the various strains of L. johnsonii is not clear, and more complete and in-depth studies are needed. In summary, L. johnsonii presents significant research potential for the treatment or prevention of disease; however, more proof is required to justify its therapeutic application. An additional study on the antibiotic resistance genes it contains is also needed to reduce the antimicrobial resistance dissemination.