The purpose of this study was to examine the metabolic, lipolytic, and cardiovascular responses to supplementation with p-synephrine alone and in combination with caffeine during resistance exercise (RE). Twelve healthy men performed a control RE protocol (6 × 10 repetitions of squats) and were randomly assigned (using a double-blind crossover design with random protocol sequencing) to a supplement sequence: p-synephrine (S; 100 mg), p-synephrine + caffeine (SCF; 100 mg of p-synephrine plus 100 mg of caffeine), or a placebo (P). Subjects reported to the lab at a standard time, consumed a supplement, sat quietly for 45 minutes, performed the RE protocol, and sat quietly for 30 minutes. Blood samples were collected at rest (T1), after sitting quietly for 45 minutes (T2), immediately following RE (T3), and 15 minutes (T4) and 30 minutes (T5) postexercise. Oxygen consumption (VO2) and heart rate (HR) data were collected throughout. Serum glycerol was significantly elevated at T2 only in S and SCF and T3 to T5 in all treatments. Nonesterified fatty acid (NEFA) concentrations did not differ between treatments. Plasma glucose was significantly elevated compared to T1 with highest area under the curve values seen in SCF. Mean VO2 and energy expenditure (EE) were significantly higher in S and SCF through 30 minutes postexercise. Fat oxidation rates favored S and SCF between 25 and 30 minutes postexercise. Mean HR during RE was significantly highest in SCF. Supplementation with S and SCF increases lipolysis primarily at rest and increases VO2, EE, and fat oxidation rates 30 minutes following RE. No HR changes were observed unless caffeine was added.