Scope: High-fat diets are a likely cause of low-grade inflammation and obesity-related pathologies. This study measures the effects of a high-fat diet, in combination with two dietary supplements—betaine and polydextrose—on metabolism and inflammation in the adipose tissue of diet-induced obese mice. Methods and Results: Forty male C57BL/6J mice are fed a high-fat diet for 8 weeks and compared with low-fat-diet-fed control animals (n = 10). For the last 4 weeks, the high-fat-diet-fed animals are supplemented with 1% betaine, 3.33% polydextrose, their combination, or plain water. Fat depots from subcutaneous and visceral adipose tissue are analyzed for inflammatory markers and nontargeted metabolomics by quantitative PCR and LC–QTOF-MS. The high-fat diet significantly increases adipose tissue inflammation in both fat depots. By metabolic profiling, clear differences are noted between low-fat-diet and high-fat-diet groups with regard to the levels of several metabolite species—primarily carnitines, lipids, and amino acids. Dietary betaine mitigates the high-fat-diet-induced IL-6 expression and significantly increases betaine and butyrobetaine levels in adipose tissue. Conclusions: The high-fat diet induces patent changes in carnitine and lipid metabolism in adipose tissue. Betaine supplementation elevates the levels of betaine and its derivatives and certain carnitine species, as reported in muscle and liver, and moderately reduces inflammation.