Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily attributed to the abnormal upregulation of hepatic lipogenesis, which is especially caused by the overactivation of the liver X receptor/sterol regulatory element-binding protein-1c (LXR/SREBP-1c) pathway in hepatocytes. In this study, we report the rational design and synthesis of a novel series of squaramides via bioisosteric replacement, which was evaluated for its inhibitory activity on the LXR/SREBP-1c pathway using dual cell-based assays. Compound 31 was found to significantly downregulate LXR, SREBP-1c, and their target genes associated with lipogenesis. Further investigation revealed that compound 31 may indirectly inhibit the LXR/SREBP-1c pathway by activating the upstream regulator sirtuin 6 (SIRT6). Encouragingly, compound 31 substantially attenuated lipid accumulation in HepG2 cells and in the liver of high-fat-diet-fed mice. These findings suggest that compound 31 holds promise as a candidate for the development of treatments for MASLD and other lipid metabolism-related diseases.