Whole genome duplication (WGD) is seen in 30-40% tumours and can lead to extensive aneuploidies. The p53 tumour suppressor prevents the progression of the G1 phase of tetraploid cells; however, around 50% of WGD events in cancer occur in p53-proficient cells. In p53-proficient tumours, abnormal activation of the E2F pathway, especially amplification of the cyclin E gene, correlates with WGD. In this work we show that cyclin E induces replication stress, which causes a prolonged checkpoint-dependent arrest in G2 phase followed by mitotic bypass and endoreduplication. Another inducer of replication stress, aphidicolin, also causes mitotic bypass with similar kinetics in the absence of cyclin E expression. Surprisingly, mitotic bypass induced by either cyclin E expression or aphidicolin requires the presence of the p53 tumour suppressor and its downstream target, the p21 cyclin dependent kinase inhibitor. Together with WEE1, p21 inhibits mitotic CDK to activate APC/CCDH1 to degrade G2 markers, leading to mitotic bypass. After mitotic bypass, cells enter a senescence-like state, but loss of p53 or expression of cyclin E can drive these cells to complete the endoreduplication cycle. Our results provide evidence that p53 can play an essential role in WGD and help explain how WGD can occur in p53-proficient cancers.