Saffron is a well-known expensive spice, which has many pharmacological properties against a variety of ailments. Saffron stigma and leaf contain apocarotenoids and bioactive phytochemicals having therapeutic potential against human disorders. Polycyclic aromatic hydrocarbons (PAHs) are one of the most common toxins in today’s aquatic environment. Benzo[a]pyrene (B[a]P), a high molecular weight PAHs prototype, and reported as a potent neurotoxicant, which is profoundly contaminating the environment. The present study investigated the therapeutic efficacy of Saffron stigma extracts and crocin, on B[a]P-induced behavioral changes, altered antioxidant activities, and neurodegeneration in zebrafish. The behavioral responses monitored through the light-dark preference test and novel tank diving test suggested that B[a]P treated zebrafish group showed alteration in anxiolytic-like behavior. Animals exhibited their native behavior when treated alone with Saffron Stigma Extract (SSE) and crocin, an apocarotenoid which also reduced the altered behavior induced by B[a]P. The SSE and crocin stimulated the antioxidant activities with an accumulation of reduced glutathione and catalase enzymes, indicating a protective role against B[a]P-induced oxidative stress and behavioral deficits. The histopathological studies showed the percentage change of pyknotic cell counts in the Periventricular Gray Zone region of the Optic Tectum was 1.74 folds high in B[a]P treated animals as compared to control. Furthermore, the treatment of SSE and crocin reduced the pyknosis process induced by B[a]P-mediated neurodegeneration, possibly due to a better protective mechanism. Future studies may reveal the detailed mechanisms of action of potent SSE and crocin like bioactive compounds having neuroprotective potentials against neurodegenerative diseases.