Microorganisms associated with termites are an original resource for identifying new chemical scaffolds or active metabolites. A molecular network was generated from a collection of strain extracts analyzed by liquid chromatography coupled to tandem high-resolution mass spectrometry, a molecular network was generated, and activities against the human pathogens methicillin-resistant Staphylococcus aureus, Candida albicans and Trichophyton rubrum were mapped, leading to the selection of a single active extract of Penicillium sclerotiorum SNB-CN111. This fungal species is known to produce azaphilones, a colorful family of polyketides with a wide range of biological activities and economic interests in the food industry. By exploring the molecular network data, it was shown that the chemical diversity related to the P. sclerotiorum metabolome largely exceeded the data already reported in the literature. According to the described fragmentation pathways of protonated azaphilones, the annotation of 74 azaphilones was proposed, including 49 never isolated or synthesized thus far. Our hypothesis was validated by the isolation and characterization of eight azaphilones, among which three new azaphilones were chlorogeumasnol (63), peniazaphilone E (74) and 7-deacetylisochromophilone VI (80).