A series of 1,3,4-thiadiazol-2-amide derivatives (5a–5y) have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and FAK inhibitors. Among all the compounds, 5h showed the most potent activity in vitro, which inhibited the growth of MCF-7 and B16-F10 cell lines with IC50 values of 0.45 and 0.31 μM, respectively. Compound 5h also exhibited significant FAK inhibitory activity (IC50 = 5.32 μM). Docking simulation was performed to position compound 5h into the FAK structure active site to determine the probable binding model. The results of antiproliferative and Western-blot assay demonstrated that compound 5h possessed good antiproliferative activity. Therefore, compound 5h with potent FAK inhibitory activity may be a potential anticancer agent.A series of 1,3,4-thiadiazol-2-amide derivatives have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and FAK inhibitors. Compound 5h possessed the most potent FAK inhibitory activity (IC50 = 5.32 μM) and anticancer activities (IC50 = 0.45 μM for MCF-7 and IC50 = 0.31 μM for B16-F10). Docking simulation was performed to insert compound 5h into the crystal structure of FAK to determine the probable binding model.