Background: The search for new drugs and molecules is crucial to advancing cancer therapy and improving patient outcomes. Significant progress has been made in cancer treatment, particularly with the development of innovative chemotherapeutic agents. However, the discovery and development of highly effective therapeutic options remain a pressing and challenging goal, highlighting the need for continued research to address the complexities of this disease. Objectives: The objective of this study is to identify new molecules capable of inhibiting the function of the Programmed Death-Ligand 1 (PD-L1) receptor. This will strengthen immunotherapeutic defense and support the immune system in the fight against tumors. The study will use molecular docking techniques, along with the prediction of pharmacokinetic properties (absorption, distribution, metabolism, excretion) and toxicity (ADMET) profiles. Methods: Molecules were retrieved from the PubChem and ChEMBL databases, while Programmed Cell Death Ligand 1 (PD-L1) was obtained from the Protein Data Bank (PDB). To investigate ligand-receptor binding interactions, molecular docking was performed using AutoDock Vina. PyMOL and Discovery Studio Visualizer (DSV) were employed for molecular visualization. The SwissADME server was used to predict the molar refractivity, saturation, and promiscuity of the hit compounds, and therapeutic chemistry criteria guided the screening process. pkCSM was utilized to assess absorption, distribution, metabolism, excretion, and toxicity (ADMET). Results: After conducting an extensive molecular docking analysis of a diverse set of structurally distinct molecules, we identified N-phenethylcinnamamide as the most promising candidate for binding to the (PD-L1) receptor. This compound exhibits strong binding to the receptor’s active site, which is critical for its functionality, demonstrating substantial binding energy. In addition to its favorable interactions, N-phenethylcinnamamide displays promising pharmacokinetic properties and an advantageous (ADMET) profile, suggesting its potential for oral administration. In order to improve its interactions with the receptor and enhance its pharmacokinetic properties, new derivatives were designed based on the structure of N-phenethylcinnamamide. This approach led to the identification of 11 novel derivatives, three of which are phytochemical compounds. These derivatives demonstrated considerable potential as PD-L1 inhibitors, exhibiting favorable pharmacokinetic properties and ADMET profiles. Conclusion: These promising findings, including molecular docking and pharmacokinetic prediction, identify molecules with high affinity for the (PD-L1) receptor and favorable pharmacokinetic properties. Through structure modification, several derivatives with improved binding energy and enhanced pharmacokinetic profiles were identified. Notably, three of these optimized molecules are already present in phytochemical compounds, highlighting the potential of plant-derived molecules in cancer immunotherapy development.