Dietary short- and medium-chain fatty acids have been shown to elevate circulating ketone bodies and confer metabolic health benefits. Cow milk fat contains these lipids in a balanced mix but in relatively low concentrations. Enriching them could amplify health benefits of dairy products. Here, we used a volatility-based workflow to produce milk fat with a 2-fold enrichment of medium- and short-chain fatty acids (referred to as MSFAT). Our proof-of-concept studies in mice demonstrated that intake of MSFAT increased circulating ketone bodies, reduced blood glucose levels, and suppressed food intake. In humans, ingestion of MSFAT resulted in increased circulating ketone bodies, trended to attenuate (p = 0.07) postprandial glucose excursion, and acutely elevated energy expenditure. Our findings show that milk products enriched with MSFAT may hold significant metabolic advantages.