In the present study, chalcones (E)-1-(10H-phenothiazine-2-yl)-3-aryl-prop-2-en-1-ones, FS1-11 were successfully synthesized via base-catalyzed Claisen-Schmidt condensation. Chemical structures of the compounds were confirmed by H-1 NMR, C-13 NMR, and HRMS techniques. Aryl part of the chalcone was changed as mono, di, and trimethoxylated phenyls. Cytotoxicities of the phenothiazine derivatives were evaluated against four human oral squamous cell carcinoma (OSCC) cell lines (Ca9-22, HSC-2, HSC-3, and HSC-4) and three human normal oral cells (HGF, HPLF, and HPC) by MTT test. The CC50 values of the compounds were calculated in the range of 0.9-109.8 mu M towards OSCC malign cell lines. Trimethoxylated compound FS6, (E)-1-(10H-phenothiazine-2-yl)-3-(2,4,5-trimethoxyphenyl)-prop-2-en-1-one, was found the most selective cytotoxic compound among the series with the highest selectivity index (SI) (SI=76.5) and potency-selectivity expression (PSE) (PSE=>1285;>1602) values. Western blot analysis demonstrated that FS6 (8-64M) induced the production of cleaved product of PARP and the activation of caspase-3 in HSC-2 cells, suggesting the induction of apoptosis by FS6. QSAR analysis suggested that the tumor specificity of the chalcones correlated with their molecular shape, volume, and electrostatic properties.