Safflower seed oil, rich in linoleic acid, has a high ω6/ω3 ratio due to its negligible ω3 content, which is potentially linked to inflammation and metabolic disorders. Despite its recognized health potential, excessive consumption of pure safflower oil can lead to adverse outcomes. To address a possible solution to solve this problem, this study optimized the ω6/ω3 ratio by blending safflower oil with ω3-rich flaxseed oil, and investigated whether the nutritional profile and health benefits of the ω3-supplemented safflower oil could be improved. Results have shown that in high-fat diet-fed mice, the optimized safflower oil significantly reduced body weight gain, fat mass, and improved glucose tolerance. The optimized safflower oil also improved the serum lipid profiles by lowering triglyceride, total cholesterol, and LDL-C levels, while reducing pro-inflammatory markers. Moreover, the adjusted ω6/ω3 ratios led to increased microbial diversity, a favorable Firmicutes/Bacteroidetes ratio, and enrichment of beneficial bacteria like Helicobacteraceae, while reducing pro-inflammatory bacteria such as Deferribacteraceae. These changes correlated with improved lipid metabolism and reduced fat accumulation. This study not only highlights a practical approach to improving safflower oil's health benefits but also provides a strategic direction for breeding programs to enhance its ω3 synthesis pathways, positioning safflower oil as a competitive and innovative alternative in the health food market.