The chemotherapeutic drug 5-Fluorouracil (5-FU) is commonly used to treat head and neck squamous cell carcinoma (HNSCC). Nonetheless, the difficulties and toxicity associated with this medicine have considerably impacted its clinical use. As a result, investigating an alternate therapeutic method that decreases 5-FU toxicity while having a synergistic effect on head and neck squamous cell carcinoma (HNSCC) is a viable option for action. Tamarix aphylla (D1) and artemisia herba alba (D2), both naturally occurring products, have been shown to suppress the development of several cancer cells, including HNSCC. This study aims to look at the combined effect of D1 and D2 and 5-FU on head and neck squamous cell carcinoma (HNSCC) and determine the apoptotic activity of this combination. The viability of cells treated with monotherapy and combination therapy was assessed using the MTT test. The researchers used flow cytometry to investigate the impact of apoptosis induction and cell cycle arrest on cells. In addition, the current study used real-time PCR to examine the expression of miR-155 and a set of specified genes. We have shown that the natural compounds D1 and D2 boost miR-155. So, our study shows that D1 and D2 may have an anti-tumorigenic effect on HNO-97 cells via a novel method. Furthermore, this study sheds light on the cellular routes through which natural compounds exert their effects.