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: human pancreatic (MIAPaCa-2), prostate (PC-3), and human hepatocellular liver carcinoma (HepG-2). Among the tested compounds, the 2,6-dichlorobenzyl derivative 5b and 2,4-dichlorobenzyl derivative 5r displayed significant cytotoxicity in PC-3 cells with IC50 values of 6 and 18 µM, respectively. Derivative 5b also showed cytotoxicity in MIAPaCa-2 (IC50: 7 µM) and HepG-2 (IC50: 19 µM) cells. Further mechanistic studies on compound 5b revealed its apoptosis-inducing activity in PC-3 cells, as evidenced by increased sub-G1 population, S-phase cell cycle arrest, nuclear morphological changes (apoptotic bodies formation), mitochondrial membrane potential loss, inhibition of pro-caspase-3, 8, and 9, cleavage of PARP-1, and a significant decrease in the Bcl-2/Bax ratio, indicating involvement of both intrinsic and extrinsic apoptotic pathways. Additionally, compound 5b inhibited VEGF-induced PC-3 cell migration (reducing wound closure from 100% to 12% at 30 µM) and angiogenesis-dependent HUVEC cell migration (reducing wound closure from 100% to 20% at 30 µM), demonstrating anti-angiogenic activity. In conclusion, semisynthetic derivative 5b exhibits significant antiproliferative, apoptotic, and anti-angiogenic potential in PC-3 cells, providing a basis for further drug-targeted studies and suggesting its potential as an anticancer therapeutic.