Colorectal cancer (CRC) is a leading cause of cancer-related mortality globally, with increasing incidence presenting significant treatment challenges. Traditional nontargeted therapies often result in high toxicity and limited efficacy, underscoring the need for improved treatment modalities. This review highlights recent advancements in drug delivery systems to enhance therapeutic outcomes for CRC. We examine innovative strategies, including computer-assisted pharmaceutical formulation, sustained-release matrices, and prodrugs, as well as targeted delivery mechanisms such as exosomes, liposomes, hydrogels, antibody-drug conjugates, and stimuli-responsive systems. These methodologies offer improved drug biodistribution, enhanced targeting of cancer cells, and reduced off-target effects, promising better clinical outcomes. Additionally, we discuss the development of novel formulations designed to optimize the delivery of therapeutic agents in advanced CRC. Ongoing clinical trials investigating these innovative systems signify a shift toward more effective patient treatment options. While challenges remain in the clinical application of these targeted therapies, continued research offers promising avenues for improving patient outcomes in CRC. This study aims to inform future strategies for managing this aggressive disease, ultimately enhancing survival rates and quality of life for affected individuals.