A series of 1,3,4-oxadiazole tethered capsaicin derivatives was prepared by using one point modification at the vanillyl-hydroxyl group of capsaicin. All the prepared capsaicinoids were evaluated for their antiproliferative activity against NCI-60 human cancer cell lines at 10 μM. Among the compounds tested, compound <b>20a</b> exhibited good cytotoxic activity against HCT-116, NCI-H460, and SKOV3 cell lines with IC<sub>50</sub> 8.55 μΜ, 5.41 μΜ, and 6.4 μΜ, respectively, compared to the parent natural product capsaicin. Further on, it significantly inhibited the colony formation in NCI-H460 in a dose dependent manner and enhanced the ROS effect. It also caused cell arrest at the S phase and induced apoptosis via suppressing the Pro parp marker. Compound <b>20a</b> exhibited an antimigratory property and suppressed the expression of the VEGF marker in a dose dependent manner. Furthermore, compound <b>20a</b> also suppressed the effects of the p-Erk, p-p38, and P-CNA makers. <i>In silico</i> studies supported the interaction of this class of compounds with the VEGFR2 protein.