Novel algicidal compounds against Microcystis aeruginosa were developed. A series of 64 thiazolidinedione (TD) derivatives were synthesized and analyzed for algicidal activity. Eleven compounds (2, 22, 38, 40, 49, 52, 54, 56, 58, 60, and 63) showed potent specific algicidal activity against M. aeruginosa with IC50 values <0.5 μM. An acute ecotoxicity test for these compounds was conducted using Danio rerio for ten days to verify their environmental impacts. Compounds 2 and 22 presented low ecotoxicity (EC50 13.59 and 8.59 μM, respectively). To evaluate the ecotoxic effect of various concentrations of compound 2, Daphnia magna were treated with 2.0, 2.3, 2.7, or 3.0 μM compound 2 for 25 days. Survival rate was 100% after 25 days in the 2.0 μM group, but declined to 96% at 8 days and 30% at 17 days in the 2.3 μM group. Our results indicate that compound 2 could be a potential bio-agent for controlling harmful algal blooms.