Longan fruit pericarp was extracted with 50% ethanol employing high pressure (500 MPa) and conventional extraction methods. Total phenolic contents of high pressure-assisted extract of longan (HPEL) and conventional extract of longan (CEL) were 20.8 and 14.6 mg gallic acid equivalents/g dry weight, respectively. Subsequently, the antioxidant activities of these extracts were analyzed employing various antioxidant model systems including 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, superoxide anion radical scavenging activity, total antioxidant capacity, and lipid peroxidation inhibitory activity. In addition, anticancer activity was also tested using HepG2, A549, and SGC 7901 cancer cell lines. HPEL showed excellent antioxidant and anticancer activities and were higher than CEL. Three phenolic compounds, namely gallic acid, corilagin, and ellagic acid, were identified and quantified by external standard methods. Compared with CEL, HPEL exhibited higher extraction effectiveness in terms of higher extraction yield, higher phenolic content, and higher antioxidant and anticancer activity with shorter extraction time. This study was focused to evaluate the antioxidant and anticancer activity of longan fruit pericarp by high-pressure treatment. The high-pressure treatment provided a better way of utilizing longan fruit pericarp as a readily accessible source of the natural anticancer and antioxidant in food and pharmaceutical industry.