The development of effective and targeted therapies for colorectal cancer remains a significant challenge. This study investigates the in vitro anticancer efficacy of a novel chitosan-based nanoemulgel co-delivering the natural compounds cynaropicrin and salicin against HCT 116 human colorectal cancer cells. An optimized nanoemulgel formulation (designated F2) was developed by incorporating an oil phase (MCT oil) containing lipophilic cynaropicrin into an aqueous phase containing hydrophilic salicin and chitosan (0.5% w/v), followed by high-shear homogenization, sonication, and incorporation into a Carbopol gel. This F2 formulation exhibited a mean particle size of 85.50 ± 0.44 nm, a low polydispersity index (PDI) of 0.272 ± 0.003, a zeta potential of -35.3 ± 0.2 mV, and high encapsulation efficiencies for cynaropicrin (91.80 ± 0.57%) and salicin (81.40 ± 0.85%), with sustained in vitro drug release over 24 hours. Cytotoxicity of F2 against HCT 116 cells, assessed by MTT assay, revealed a potent dose-dependent reduction in cell viability, with an IC₅₀ value of approximately 42 µg/mL. Mechanistic studies demonstrated that the observed cytotoxicity was mediated, at least in part, through the induction of apoptosis. Annexin V-FITC/PI staining followed by flow cytometry showed a significant, concentration-dependent increase in both early and late apoptotic cell populations, with an estimated apoptosis IC₅₀ of ~55 µg/mL. Furthermore, the nanoemulgel significantly inhibited HCT 116 cell migration in a dose-dependent manner, as determined by the scratch (wound healing) assay. At 48 hours, the highest concentration of F2 (5.00 µg/mL) reduced wound closure to 5.0%, compared to 28.3% in untreated controls. These findings highlight the potent cytotoxic, pro-apoptotic, and anti-migratory effects of the cynaropicrin and salicin co-loaded nanoemulgel, suggesting its promising potential as a multi-modal therapeutic strategy for colorectal cancer.