Glycyrrhetic acid (2, 3β-hydroxyl-11-oxo-olean-12-ene-29-oic acid), a pentacyclic triterpenoid isolated from Glycyrrhiza glabra, is known to possess a wide range of biological activities. Herein, we report the synthesis and antiproliferative activity of 3-O-ether derivatives of glycyrrhetic acid. The cytotoxicity of the prepared derivatives was investigated in three cancer cell lines, including human pancreatic (MIAPaCa-2), prostate (PC-3) and human hepatocellular liver carcinoma (HepG-2). Amongst the tested compounds, the 2,6-dichlorobenzyl 5b and 2,4-dichlorobenzyl derivative 5r displayed significant cytotoxicity in PC-3 cells with IC50 values of 6 and 18 μM, respectively. The dichlorobenzyl derivative 5b also displayed cytotoxicity in MIAPaCa-2 (IC50: 7 μM) and HepG-2 cells (IC50: 19 μM). Further, compound 5b was investigated for apoptosis-induction by cell cycle analysis, nuclear morphological changes and mitochondrial membrane potential loss in PC-3 cells. Compound 5b led to an increase in the sub-G1 population in PC-3 cells, which is indicative of its apoptotic properties. Interestingly, compound 5b also arrested the S-phase of the cell cycle. The nuclear morphology of PC-3 cells after treatment with compound 5b was also investigated which confirmed the formation of apoptotic bodies. Compound 5b induced apoptosis through both intrinsic and extrinsic apoptotic pathways in PC-3 cells, which was confirmed by mitochondrial membrane potential loss, inhibition of pro-caspase-3, 8 and 9 and cleavage of PARP-1. Furthermore, there was a significant decrease in the Bcl-2/Bax ratio induced by compound 5b in PC-3 cells. Interestingly, compound 5b also inhibited the VEGF-induced PC-3 cell migration and decreased the wound closure percentage from 100 to 12% at 30 μM. Similarly, compound 5b inhibited the angiogenesis-dependent cell migration in HUVEC cells and decreased wound closure from 100 to 20% at 30 μM, indicating its anti-angiogenic activity.