Two new quinazolinone nitriles (1 and 2) and one new indole alkaloid (3), together with 13 known compounds, were isolated from the deep-sea-derived Penicillium viridicatum MCCC 3A00265. Their structures were determined by extensive spectroscopic analysis, with the absolute configurations established by comparing experimental and calculated electronic circular dichroism (ECD) and optical rotation (OR) data as well as biogenetic considerations. Viricyanoamides A and B (1 and 2) are the sole representatives of quinazolinones featuring a nitrile group, while solitumidine F (3) incorporates a rare pyrrolidinedione unit as an indole terpenoid. In particular, compounds 2 and 10 exhibit significant activity in reactivating mutant p53 at 10 μM, indicating their potential for application in cancer therapy.