Herein we report the regioselective synthesis of podophyllotoxin-Glycosyl triazole hybrids catalysed by Ag(I)--heterocyclic carbene (Ag(I)-NHC) in a short reaction time (∼30 min) at ambient conditions. In principle, it is the first report of Click alkyne-azide cycloaddition catalysed by Ag(I)-NHC catalyst and moreover, this new methodology yielded good results when compared with traditional CuAAC in terms of reaction time and selectivity. The synthesised compounds were further explored for anticancer activity against four human cancer cell lines Du145, HeLa, A-549, and MCF-7 and found that these synthesised compounds possess significant anticancer activity. Further, the compounds and were identified as promising leads due to their better activity across all cell lines than that of the standard drug etoposide. Molecular docking studies of 5a & 5e with DNA Topoisomerase-II were revealed that the free energy calculations of active compounds were in good agreement with observed IC values.