Star apple (Chrysophyllum cainito L.), or Apple-nam in Thai, is a medium-sized tree in the Sapotaceae family. It is native to Middle America and distributed in Thailand and Southeast Asia. It has antioxidation, anti-inflammatory and anti-diabetic properties. The active compounds in star apples are flavonoids. This research aimed to study the biological activities and chemical constituents of crude extract and active fractions from the leaves of star apples. The leaf powder was defatted with dichloromethane and further extracted with ethanol using ultrasound-assisted extraction. The ethanol extract was separated by quick column chromatography given 7 fractions (CCE1-CCE7). The total phenolic content and antioxidant activity of the extract and chromatographic fractions were determined. The active fractions were further studied for tyrosinase inhibition, collagenase inhibition and cell proliferation properties. The result showed that the highest total phenolic content was observed in ethanol extract. The high polar fraction, CCE6, displayed the highest antioxidation activity with radical scavenging of 0.34 ± 0.01 mg AAE/mL in the DPPH assay and a FRAP value of 1.36 ± 0.01 mg AAE/mL in the FRAP assay. The CCE6 also exhibited the highest anti-tyrosinase and anti-collagenase activities with a percentage of 67.14 ± 1.34 and 70.32 ± 2.88, respectively and showed the best activity in cell proliferation with a percentage of 24.68 ± 2.94. The analysis of the components using the negative ionization LC-MS technique revealed that gallic acid and quercetin-3-galactoside are the major constituents in the ethanol extract. While the fraction CCE6 showed glucosyl (2E,6E,10x)-10,11-dihydroxy-2,6-farnesadienoate and p-mentha-1,3,5,8-tetraene as the predominant compounds. HIGHLIGHTS The ethanol extract was prepared using ultrasound-assisted extraction. The first report of tyrosinase and collagenase inhibition, as well as cell proliferation properties, of the cainito leaves extract and chromatographic fractions. The major components of the ethanol extract of cainito leaves in Thailand and its active fraction by LC-MS technique were reported for the first time. GRAPHICAL ABSTRACT