The impact of a soluble complex (SC) of curcumin (CuR) synthesized using hot melt (HM) and hot-melt extrusion (HE) technologies on adenocarcinoma cells for the treatment of colorectal cancer by enhancing CuR solubility is investigated in this work. In silico molecular modelling, solubility, drug release, and physicochemical analysis were all part of the phase solubility (PS) study, which featured a novel dyeing test and a central composite design to optimize the best complex (CDD). The optimal HE-SC (1 : 5) enhances solubility (0.8521 ± 0.016 mg·mL−1) and dissolution (91.87 ± 0.208% at 30 min), and it has an ideal stability constant (309 and 377 M−1) at 25 and 37°C and an AL type of isotherm, implying 1 : 1 stoichiometry according to the findings. An intermolecular hydrogen bond that has not undergone any chemical change and has resulted in the complete conversion of the amorphous form aids in the creation of SC. In vitro cytotoxicity was measured at IC50 on the SW480 (72 M·mL−1) and Caco-2 (40 M·mL−1) cells. According to apoptotic studies, apoptosis was responsible for the vast majority of cell death, with necrosis accounting for a small proportion of the total. In vivo toxicity was established using a zebrafish model, and a western blot examination revealed apoptosis at the molecular level. It was argued that the novel formulations developed using HE technology are more significant and effective than existing pure CuR formulations.