Different agro-industrial materials were screened for their performance on production of mycophenolic acid (MPA) by two strains of Penicillium roqueforti (AG101 and LG109) under solid-state fermentation (SSF). Sugarcane bagasse followed by corn stalks and rice bran were the most favorable substrates supporting the MPA production. The maximum MPA concentration was achieved at initial moisture content 70% for the first substrate and 80% for the other substrates. Enrichment of the solid substrate with a modified Czapek's broth promoted a greater MPA concentration than that enriched with mineral salt solution. The AG101 and LG109 strains were improved to produce higher significant MPA titers on solid substrate by subjecting the spores to irradiation by UV light (254 nm) for 120 and 90 min, respectively; and gamma rays at 0.75 KGy. The highest MPA-producing ability of both irradiated strains was observed on sugarcane bagasse and it was increased by 1.57-1.72 fold when irradiated with UV rays and by 1.74-1.92 fold when irradiated with gamma rays, as compared with the non-irradiated cultures. These findings indicate the future possibility to reduce the cost of producing fermentation-based drugs.