Purpose: This study was conducted to investigate impacts of potential anticancer (associated with apoptosis and caspase pathways) of two newly synthesized derivatives of pillar[5]arene, named as d-Q-P5 and p-Q-P5, on Squamous cell carcinomas of the head and neck (HNSCC) cells. Materials and methods: The MTT method was used to determine the IC50 doses of the derivatives on HNSCC cells, and the changes in gene expression were analyzed by real-time polymerase chain reaction (qPCR). The apoptosis change was confirmed by flow cytometry analysis. Results: The results showed that the d-Q-P5 and p-Q-P5 effectively inhibited the proliferation of the cells by upregulating proapoptotic genes (Bax, Bad, p53, Bak, and Apaf-1) and genes involved in the caspase pathway (Casp2, Casp3, and Casp9), while downregulating the antiapoptotic gene (Bcl-2). Conclusions: This study is the first to demonstrate the potential anticancer effects of these two agents on HNSCC cells by positively regulating apoptosis gene expression.