Genome mining of cryptic natural products (NPs) remains challenging, especially in filamentous fungi, owing to their complex genetic regulation. Increasing evidence indicates that several epigenetic modifications often act cooperatively to control fungal gene transcription, yet the ability to predictably manipulate multiple genes simultaneously is still largely limited. Here, we developed a multiplex base-editing (MBE) platform that significantly improves the capability and throughput of fungal genome manipulation, leading to the simultaneous inactivation of up to eight genes using a single transformation. We then employed MBE to inactivate three negative epigenetic regulators combinatorially in Aspergillus nidulans, enabling the activation of eight cryptic gene clusters compared to the wild-type strains. A group of novel NPs harboring unique cichorine and polyamine hybrid chemical scaffolds were identified, which were not reported previously. We envision that our scalable and efficient MBE platform can be readily applied in other filamentous fungi for the genome mining of novel NPs, providing a powerful approach for the exploitation of fungal chemical diversity.