Thyroid cancer is the most frequent endocrine malignancy, which accounts for nearly 1% of all the cancer worldwide. Crocin has a diverse biological function, such as anti-cancer, anti-inflammatory and antioxidant functions, specifically in the respiratory related diseases. Using in vitro techniques, this work was intended to illuminate the anti-cancer effect of crocin in follicular thyroid carcinoma (FTC) (FT 133 cells), and the potential molecular mechanism convoluted. The outcome of the present work showed that crocin was able to prevent the proliferation and triggering the apoptosis in a dose-dependent mode, of FTC-133 cells by methyl thiazolyldiphenyl-tetrazolium bromide and staining assay (acridine orange/propiduim iodide [PI], 4 ',6-diamidino-2-phenylindole, and PI dye). Crocin did not show toxicity to the normal thyroid (PCCL3) cells. Crocin-induced reactive oxygen species, mitochondrial membrane potential activity, caspase-8 and -9, lipid peroxidation (thiobarbituric acid reactive substances) activity while suppressing antioxidant activity (superoxide dismutase, catalase, and glutathione) in FTC-133 cells. In addition, crocin was also participated in a halting of the proteins related to cell cycle, cyclin D1, and pro-apoptotic proteins; Bax and caspase-3 expression, together with the elevation of anti-apoptotic factor Bcl-2. Further, crocin have a dual inhibition of two major pathways, nuclear factor-kappa B, extracellular signal-regulated kinase, and janus kinase-signal transducer and activator of transcription signaling pathways. In conclusion, crocin can inhibit follicular thyroid carcinoma proliferation and promote cell apoptosis.