Objective <p>Recent studies indicated that natural bioactive chemicals can alter signaling molecules associated with or interacting with the Notch pathways in cervical cancer. Thus, the objective of the current study was to examine the potential of erianin, a natural compound from <i>Dendrobium chrysotoxum</i>, in cervical cancer SiHa cells, with an emphasis on apoptosis induction and exploring the assessment of the Notch signaling pathway.</p> Methods <p>The inhibitory effects of erianin on cell viability were evaluated using MTT tests. Cell cycle analysis was performed to elucidate the antiproliferative mechanism of erianin. ROS generation, Cytochrome C assay, caspase-3, -8, -9 test, Annexin V/FITC staining, and qRT-PCR were performed to assess the apoptotic potential of erianin. To further investigate the mechanistic role of erianin, expression levels of key targets of the Notch pathway (Notch1, DLL4, Jagged1) were measured in vitro by qRT-PCR, and the binding efficacy by of key targets of the Notch pathway was measured by the CB-Dock molecular docking approach.</p> Results <p>The IC₅₀ value of erianin in SiHa cells was 51.25 ± 2.81 nM while, no cytotoxicity was seen at the optimal dose as observed in normal HEK293 cells. Erianin effectively induced ROS generation, G2/M cell cycle arrest and decreased the ability of mitochondria to survive by increasing the levels of cytochrome C. Furthermore, erianin treatment stimulated caspase-3, -8, and-9 levels in SiHa cells and the number of apoptotic cells. Erianin also decreased the expression of Notch1, Jagged1 and DLL4 in SiHa cells, and demonstrated a strong binding efficacy.</p> Conclusions <p>Thus, our results provide preliminary evidence that erianin may serve as a promising anticancer candidate for the treatment of cervical cancer by inhibiting the Notch signaling pathway. However, further validation is required to establish a definite mechanistic link.</p>