Polyurethane is an excellent implant biomaterial due to its elasticity, flexibility, resistance to abrasions and chemicals, and highly hydrophobic nature. The risk of hydrophobic nature is a significant drawback for an ideal drug delivery system. To enhance the hydrophilicity and compatibility of polyurethane via surface modification, such as (1) Introducing salicylic acid into the polymer backbone can create voids for the release of drugs from the matrix. (2) Doping silver onto HNTs by a simple one-pot precipitation method can enable silver to rupture the nucleus of cancer cells and induce ROS formation. The polyurethane and its mixed matrix were cast into the film to improve the initial effect of the drug, duration, and dosing than other conventional methods. The benefits of surface modification and thin film technology resulted in degradability, cytocompatibility, and excellent anticancer activity. The in vitro release studies depict that the letrozole-loaded film has a sustained release effect for a longer period based on the swelling ratio. The MTT assay showed that the [email protected] film could cause THP-1 cell death due to silver, polyols of PU, and HNTs. Salicylic acid played a vital role in increasing the antibacterial activity of the film. Furthermore, the increased oxidative stress was seen in [email protected]/Let film due to the biomaterial's active presence. Thus, [email protected]/Let a film is a potential approach for producing an implantable anticancer drug delivery system for the future with higher tumor cell death and prolonged drug release.