A new series of substituted aryl carboximidamide VIa-o was designed and synthesised. IR, ¹H NMR, ¹³C NMR as well as elemental microanalysis were used to confirm the structures of the new compounds. The antiproliferative effect of the news compounds against four cancer cell lines was investigated. Compounds VIc, VIg, VIj, VIk, VIm, and VIo were the most potent ones with GI₅₀ ranging from 34 to 48 nM, compared with erlotinib (GI₅₀ of 33 nM). The utmost potent compounds were further examined for their efficacy as EGFR inhibitors, and the results showed that the tested compounds inhibited EGFR with IC₅₀ ranging from 83 nM to 112 nM when compared to the reference erlotinib (IC₅₀ = 80 nM). Moreover, the six most potent compounds had promising VEGFR-2 inhibitory activity, with IC₅₀ ranging from 1.8 nM to 11.4 nM compared with sorafenib, (IC₅₀ = 0.17 nM).