Background <p>Phytochemicals showed potential application as anticancer agents. In the current investigation, quercetin, cold-pressed orange peel oil, and their mixture in their natural state and in micellar dispersion and nanoemulsions were examined for their activity to induce HCT116 and Caco-2 colorectal cancer cells to apoptosis.</p> Materials and methods <p>Gas chromatographic analysis was used to characterize orange oil composition. Different solubilization systems were developed in order to incorporate these phytochemicals into a self emulsifyable concentrate that spontaneously forms micellar dispersions and nanoemulsions upon titration into water. Different evaluations were performed to characterize the nanoemulsions. Some biological evaluations including cytotoxicity, apoptosis, protein expression, and reactive oxygen species were also performed.</p> Results <p>Gas chromatographic analysis showed that <i>d</i>-limonene is the major constituent contained (89%) of orange oil. Systems composed of a single surfactant and a mixture of two surfactants and a cosurfactant were able to incorporate 500 mg quercetin and 5% orange oil in 100 ml nanoemulsions. The particle size of the nanoemulsions ranges between 12 ± 0.09 nm and 27 ± 0.1 nm, depending on the incorporated phytochemical, with z-potential value in the range of -0.9 mV. Encapsulation efficiency for both quercetin and orange oil was &gt; 93% and the release from the formulations exhibited a controlled, time-dependent profile for both quercetin and orange oil. Quercetin and orange oil in their natural state showed cytotoxic and apoptotic activity against the tested colorectal cancer cells, which is enhanced upon combining these phytochemicals. The micellar dispersions and nanoemulsion form of these phytochemicals showed enhanced cytotoxicity, apoptotic activity, and ROS levels compared to their unformulated natural states indicating the powerful effect of nanoparticles. Moreover, nanoemulsion fabricated with a mixture of two surfactants showed the best cytotoxic and late apoptotic activity through downregulation of CDC25A, PI3k, and Bcl-2 expression levels and upregulation of Bax expression compared to nanoemulsion made using a single surfactant.</p> Conclusions <p>Combining quercetin and orange oil in a co-fabricated nanoemulsion could be considered a promising formula that could be examined as an adjuvant to the protocol-prescribed drugs to enhance their activity against colorectal cancer cells.</p>