Cancer is recognized as a worldwide public health concern. Therefore, there is a continuous quest to discover new effective medications with less side-effects. In recent years, researchers have shown an increased interest in medicinal plants as several plant species have shown promising biological activities. Thus, we seek to investigate three medicinal herbs that are commonly-found in the Middle Eastern region and yet have not been explored in depth including plants belonging to the Rhamnaceae, Polygonaceae, and Apocynaceae plant families. Initially, we investigated using three types of cancer cell lines for breast, colorectal, and liver cancers. We performed High Content Imaging (HCI)-Apoptosis Assay and ApoTox-Glo™ Triplex Assay on KAIMRC2 and HCT8 cell lines. The highest activity of HCI-Apoptosis Assay was with Calligonum comosum and Ziziphus nummularia in ethanol followed by Calotropis procera and Ziziphus nummularia in ethyl acetate. The IC₅₀ values for the families of Rhamnaceae, Polygonaceae, and Apocynaceae in HepG2 and HCT8 cell lines ranged from 0.089 to 9.84 mg/mL and 0.080 to 15.08 mg/mL, respectively. Further screening was conducted on an additional two cell lines namely the MDA-MB-231 and KAIMRC2 for selected seven extracts with the highest activity having IC₅₀ values ranged from 0.058 to 0.51 mg/mL and 0.029 to 0.19 mg/mL, respectively. Continuous scientific investigations to isolate and characterize the potent bioactive phytochemical(s) are warranted.