Cocoa-phytochemicals have been related to the health-benefits of cocoa consumption. Metabolomics has been proposed as a powerful tool to characterize both the intake and the effects on the metabolism of dietary components. Human urine metabolome modifications after single cocoa intake were explored in a randomized, crossed, and controlled trial. After overnight fasting, 10 subjects consumed randomly either a single dose of cocoa powder with milk or water, or milk without cocoa. Urine samples were collected before the ingestion and at 0-6, 6-12, and 12-24-h after test-meals consumption. Samples were analyzed by HPLC-q-ToF, followed by multivariate data analysis. Results revealed an important effect on urinary metabolome during the 24 h after cocoa powder intake. These changes were not influenced by matrix as no global differences were found between cocoa powder consumption with milk or with water. Overall, 27 metabolites related to cocoa-phytochemicals, including alkaloid derivatives, polyphenol metabolites (both host and microbial metabolites) and processing-derived products such as diketopiperazines, were identified as the main contributors to the urinary modifications after cocoa powder intake. These results confirm that metabolomics will contribute to better characterization of the urinary metabolome in order to further explore the metabolism of phytochemicals and its relation with human health.