UV-induced DNA damage plays a key role in the etiology of certain diseases. The ability of blueberry anthocyanins and anthocyanidins (BA) to protect cellular DNA from UV-induced damage was investigated. BA were extracted by water (BAW), ethanol (BAE) or methanol (BAM). These extracts partially restored proliferation of UV-irradiated HepG2 cells as shown by MTT assay. Treatment with BA extracts at 75 μg/ml decreased reactive oxygen species and decreased DNA damage by tail moment of comet assay and expression of γH2AX in situ. BAM significantly decreased gene and protein expression of p53, phospho-p53 (Ser15), and p21 in UV-irradiated HepG2 cells. BA thus efficiently protects cells from DNA damage in vitro. Blueberry may potentially be used as a good source of naturally radioprotective agents.