Colorectal cancer (CRC) remains a major contributor to global cancer-related mortality, with rising incidence observed in several regions, including Saudi Arabia. This review compiles and critically analyzes recent preclinical research from Saudi-based institutions that investigates the anti-CRC potential of natural and synthetic compounds. Numerous natural products such as Nigella sativa, Moringa oleifera, Curcuma longa, and marine-derived metabolites have demonstrated cytotoxic effects through pathways involving apoptosis induction, reactive oxygen species (ROS) generation, and inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and cyclooxygenase-2 (COX-2). In parallel, synthetic and semi-synthetic agents, including C4–G4 (semi-synthetic hybrids designed from flavonoids and benzoxazole scaffolds that act as dual epidermal growth factor receptor (EGFR)/COX-2 inhibitors)), oxazole derivatives, and camptothecin-based nanocarriers, exhibit promising anti-tumor activity via molecular targeting of cyclin-dependent kinase 8 (CDK8), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and β-catenin pathways. Selected in vivo studies primarily utilizing xenograft and chemically induced rodent models have shown reductions in tumor volume and modulation of apoptotic and inflammatory biomarkers. Additionally, green-synthesized metallic nanoparticles (NPs) and polyethylene glycol (PEG)-modified carriers have been investigated to improve bioavailability and tumor targeting of lead compounds. While these findings are encouraging, the majority remain in preclinical phases. Limitations such as poor solubility, lack of pharmacokinetic data, and absence of clinical trials impede translational progress. This review highlights the need for standardized evaluation protocols, mechanistic validation, and region-specific clinical studies to assess efficacy and safety. Given Saudi Arabia’s rich biodiversity and growing research capacity under national strategies like Vision 2030, the country is well-positioned to contribute meaningfully to CRC drug discovery. By integrating bioactive natural products, rationally designed synthetics, and advanced delivery platforms, a pipeline of innovative CRC therapeutics tailored to local and global contexts may be realized.

Colorectal cancer (CRC) is a major public health concern in Saudi Arabia, with rising incidence rates and limited treatment responsiveness in advanced stages. This review presents an in-depth analysis of preclinical and experimental research conducted within the region, focusing on natural products and synthetic compounds with therapeutic potential. Plant-derived extracts, marine bioactives, and engineered molecules have shown efficacy in inducing apoptosis, arresting the cell cycle, and modulating critical signaling pathways in CRC models. Additionally, novel nanotechnology-based delivery systems and combination therapies are emerging as promising approaches to overcome drug resistance and improve treatment precision. This review highlights translational research directions and underscores the need for clinical validation of these compounds to enhance CRC management and patient outcomes in Saudi Arabia.