Cancer remains a formidable global healthcare challenge, driving relentless research efforts. Among the diverse compounds explored for their potential in combating cancer, α,β‐unsaturated compounds have exhibited intriguing biological activities, including anticancer properties. In this study, we embarked on synthesizing novel α,β‐unsaturated compounds anchored by a phenylacrylonitrile base using the Knoevenagel reaction. Our investigation delved into the cytotoxicity of these compounds, where two standouts, 3 f and 3 g, demonstrated remarkable antiproliferative efficacy comparable to the established chemotherapy drug, doxorubicin, when tested against various cancer cell lines. Additionally, the influence of these compounds was evident as DNA fragmentation became apparent after a mere 24‐hour exposure. Molecular docking analysis unveiled a compelling interaction between our synthesized compounds and the P38‐α receptor, a pivotal player in the Mitogen‐Activated Protein (MAP) kinase 14 pathway. This revelation suggests the potential of our compounds to target this receptor, opening new avenues for further exploration. Our research not only underscores the promising anticancer potential of these α,β‐unsaturated compounds but also identifies a specific molecular target, P38‐α, paving the way for future investigations in cancer therapeutics. In an ever‐evolving quest to combat cancer, this study contributes valuable insights that may hold the key to innovative treatment strategies.