We postulate that metabolic conditions that develop systemically during exercise (high blood lactate and high nonesterified fatty acids) are favorable for energy homeostasis of the heart during contractile stimulation. We used working rat hearts perfused at physiological workload and levels of the major energy substrates and compared the metabolic and contractile responses to an acute low-to-high work transition under resting versus exercising systemic metabolic conditions (low vs. high lactate and nonesterified fatty acids in the perfusate). Glycogen preservation, resulting from better maintenance of high-energy phosphates, was a consequence of improved energy homeostasis with high fat and lactate. We explained the result by tighter coupling between workload and total β-oxidation. Total fatty acid oxidation with high fat and lactate reflected increased availability of exogenous and endogenous fats for respiration, as evidenced by increased long-chain fatty acyl-CoA esters (LCFA-CoAs) and by an increased contribution of triglycerides to total β-oxidation. Triglyceride turnover (synthesis and degradation) also appeared to increase. Elevated LCFA-CoAs caused high total β-oxidation despite increased malonyl-CoA. The resulting bottleneck at mitochondrial uptake of LCFA-CoAs stimulated triglyceride synthesis. Our results suggest the following. First, both malonyl-CoA and LCFA-CoAs determine total fatty acid oxidation in heart. Second, concomitant stimulation of peripheral glycolysis and lipolysis should improve cardiac energy homeostasis during exercise. We speculate that high lactate contributes to the salutary effect by bypassing the glycolytic block imposed by fatty acids, acting as an anaplerotic substrate necessary for high tricarbocylic acid cycle flux from fatty acid-derived acetyl-CoA.