Natural products (NPs) and their derivatives play a pivotal role in drug discovery due to their complexity and diversity. The strategies to rapidly generate NP-like compounds offer unique opportunities to access bioactive compounds. Here we present a new approach, precursor-assisted biosynthesis (PAB), for the creation of NP-like compounds by combination of artificial supplementation of common precursors and divergent post-modifications of precursor-deficient fungi. This method was applied to construct a meroterpenoid-like compound collection containing 43 compounds with diverse molecular scaffolds. Extensive bioactive screening of the collection revealed novel STING (stimulator of interferon genes) inhibitors, cytotoxic and antifungal compounds. This result indicates that PAB is an effective methodology for producing compound collections for the purpose of drug discovery.