The anti-inflammatory, antioxidant properties of many probiotic microbes and their ability to modulate the composition of intestinal flora suggest that they have the potential to prevent and/or treat nonalcoholic fatty liver disease (NAFLD). The present study provides evidence that Lactiplantibacillus plantarum HP-B1280 can significantly reduce fat accumulation and inflammatory cell infiltration within the hepatocytes of fatty liver mice and thus may have potential application value in the prophylaxis and treatment of NAFLD disease. HP-B1280 also exhibits an extremely high level of resistance to acids and bile salts. The fermentation broth of HP-B1280 cultures is effectively suppresses the growth of a variety of common human pathogens. A comprehensive analysis of the complete genome sequence of L. plantarum HP-B1280 was conducted. Results indicated that the genome of L. plantarum HP-B1280 was devoid of resistance genes, drug resistance genes, as well as virulence factors. The annotation of the genome provides a foundation for further studies on the mechanism underlying the prevention and treatment of NAFLD by L. plantarum HP-B1280. In summary, the findings of the present study provides valuable insights into the potential use of probiotics, such as L. plantarum HP-B1280 in the amelioration and prophylaxis of NAFLD.