Abstract Cancer-fighting needs more effective and targeted drugs, desirably with least side-effects and from natural bases. The assessment and synergistic actions of multiple anticancer drug candidates were investigated. Fucoidan (Fu) was extracted from Sargassum cinereum, which was attained from the Saudi Red-Sea coast. The extract of Ganoderma lucidum or Reishi mushroom (Re) was achieved, intermixed with Fu solution, and they were used for reducing/decorating/capping selenium nanoparticles (SeNPs). The infrared analysis of produced/synthesized agents emphasized their biochemical structures and interactions. The decorated Fu/Re/SeNPs had negative (−30.6 mV) zeta potential and the SeNPs mean particle size was 6.5 nm. The transmission imaging of SeNPs indicated their spherical profiles and well-dispersion within Fu/Re composite. The anticancer potentiality of Fu/Re and Fu/Re/SeNPs against human colorectal adenocarcinoma cells was investigated using MTT, 4′,6-diamidino-2-phenylindole staining and comet assay. Both composites exhibited potent bioactivities toward adenocarcinoma cells; the reduced cells survival was detected with IC50 of 57.82 and 16.43 µg·mL−1 for Fu/Re and Fu/Re/SeNPs, respectively. The constrained apoptosis was notably observed from treated cells with the composites; substantial molecular damages were also verified via the comet assay, especially in Fu/Re/SeNPs treated cells. The innovative innocuous composite from Fu/Re/SeNPs is highly recommended to deactivate/destruct colorectal adenocarcinoma cells.