Obesity is associated with chronic inflammation that affects various organs in the body, including the reproductive system, which is a key factor in male infertility. 1-Deoxynojirimycin (1-DNJ) is a natural alkaloid in mulberry leaves, which has anti-inflammatory capabilities, yet, it's effects on obesity-induced inflammation-related male infertility remain unclear. Therefore, this research investigates the underlying mechanism by which 1-DNJ may mitigate fertility impairment in male mice caused by obesity-related inflammation. Male mice with high-fat diet (HFD)-induced obesity were treated with 1-DNJ or metformin for 8 weeks. Metabolic profiles were evaluated by enzyme method. Reproductive capacity was assessed by sperm viability, motility and counts, immunohistochemistry was performed to evaluate the testicular damage caused by obesity and inflammation. The inflammation was assessed by measuring the levels of tumor necrosis factor α (TNFα), interleukin 1β (IL-1β), and interleukin 6 (IL-6). The activation of IκB kinase β (IKKβ) and nuclear factor κB (NF-κB) was examined using western blot and immunohistochemistry. HFD induced obesity in mice with obvious lipid metabolism disorder. The obese male mice had a decreased testosterone level, impaired sperm motility, and increased inflammatory factors. 1-DNJ treatment improved the testosterone level in the obese mice, ameliorated the testicular structure damage and improve sperm viability. In addition, 1-DNJ treatment inhibited IKKβ/NF-kB signaling pathway and reduced inflammation in obese mice. 1-DNJ can improve the fertility of obese men by reducing obesity as well as obesity-induced inflammation. These findings provide new insights for 1-DNJ to alleviate inflammation caused by obesity and provide future possibilities for treating male infertility.© 2024. The Author(s).