p-Synephrine is a natural protoalkaloid present in Citrus aurantium, which is used in the dietary supplement market for weight control and weight reduction due to its supposed thermogenic effects and its influence on metabolism. The purpose of this research was to determine the effects of p-synephrine supplementation in healthy physically active adults on health biomarkers and physical performance. Following the Preferred Report Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, studies indexed in the following three databases were systematically reviewed: Medline (PubMed), SCOPUS and CINAHL. Original studies published from 2010 to 15 August 2025 with a controlled trial design comparing p-synephrine supplementation with a control group were included. The PEDro scale and the McMaster questionnaire were used to analyze methodological quality, and the Cochrane bias assessment tool was used. From the 103 records identified, only 7 met the inclusion criteria. Overall, p-synephrine caused a significant increase (p < 0.05) in fat oxidation. At the same time, the supplement significantly decreased (p < 0.05) carbohydrate oxidation and exhibited a non-significant tendency (p > 0.05) to increase tympanic temperature. However, no changes were observed in cardiovascular biomarkers, anthropometric parameters, glycemia or total cholesterol. Regarding sports performance, p-synephrine supplementation significantly improved (p < 0.05) the number of repetitions and the maximum carbon dioxide volume. On the other hand, non-significant increases (p > 0.05) were observed in mean velocity and maximum oxygen volume. In conclusion, p-synephrine is a safe supplement that modulates the metabolism of certain energy substrates, specifically by increasing fat oxidation and decreasing carbohydrate oxidation during exercise, providing an indirect ergogenic effect. Finally, no serious adverse effects were reported. These findings suggest that p-synephrine may be a safe and potentially useful supplement, although further studies are needed to confirm its long-term efficacy and metabolic impact.