Cancer has become the second main reason for worldwide disease-related deaths. There is a need to take remedial action to combat this condition and to develop new drugs and therapies for its treatment. Accordingly, it was decided to prepare and perform the anticancer activity of novel coumarin derivatives. The compounds 3a-3j were prepared from the reaction between 1a-1b and 2a-2e. The structures of 3a-3j were elucidated with the help of physical and spectral analysis. The sulforhodamine B (SRB) colorimetric method was adopted to assess the anticancer potential of 3a-3j with respect to HCT-116 and MCF-7 cell lines. The 3a derivative was the most promising compound that had IC50 of 1.93 µM and 1.25 µM concerning HCT-116 and MCF-7, respectively. However, its activity was almost 40% less than the doxorubicin. Accordingly, it was concluded that more effective anticancer agents can be developed by incorporating phenolic –OH group in the coumarin moiety and substituting a fluorine atom at an appropriate place of 3a-3j.