Guaiazulene and related derivatives were famous for diverse biological activities. In an effort to discover new highly efficient candidate drugs derived from guaiazulene, four series of guaiazulene derivatives were designed, synthesized, and evaluated for antiproliferation, antiviral, anti-inflammatory and peroxisome proliferatorsactivated receptor γ (PPARγ) signalling pathway agonist activities. Among them, two guaiazulene condensation derivatives showed selective cytotoxic activities towards K562 cell with IC 50 values 5.21 μM and 5.14 μM, respectively, accompanied by slight effects on normal cell viability. For the first time, one guaiazulene derivative from series I exhibited potent antiviral activity towards influenza A virus with IC 50 of 17.5 μM. A guaiazulenebased chalcone showed higher anti-inflammatory activity than positive drug indomethacin with an inhibitory rate of 34.29 % in zebrafish model in vivo. One guaiazulene-based flavonoid could strongly agitate PPARγ pathway at 20 μM, indicating the potential of guaiazulene derivatives to reduce obesity development and ameliorate hepatic steatosis. Preliminary in silico ADME studies predicted the excellent drug-likeness properties of bioactive guaiazulene derivatives.