Red yeast rice (Monascus fermented rice) contains monacolin K (MK), an HMG-CoA reductase inhibitor. Red yeast rice (RYR) contains a variety of other potential biological active molecules. The objective of this study was to study the effects of a crude extract and a fraction that contained the red azaphilione pigments rubropunctamine and monascorubramine and compare this to pure monacolin K (MK) in a hepatocarcinoma cell line (HepG2). An MTT proliferation assay showed that RYR crude, MK, and fraction 4 (red pigments) reduced cell growth in a dose-dependent manner with 72h LC50 values of 0.734±0.015mg/mL for RYR crude, 8.842±1.703μg/mL for MK and 0.039±0.002mg/mL for fraction 4. Cell death was determined using three distinct flow cytometry assays for apoptosis (sub-G1 cell cycle analysis, TUNEL apoptosis assay and multi-caspase apoptosis assay). The TUNEL apoptosis assay after 72h of treatment showed a larger apoptotic cell accumulation after MK treatment (22.45±0.60%) and RYR crude extract (18.22±0.62%) compared to fraction 4 (7.29±0.09%). After 72h treatment, fraction 4 induced cellular senescence in a dose dependent manner. Cell had morphological changes and increase in β-galactosidase activity, a marker of senescence and causes irreversible growth arrest. This is the first report describing cellular senescence of red monascus pigments extract isolated from RYR.