The co-occurrence of cyanobacterial harmful algal blooms and contaminants is an increasing environmental concern in freshwater worldwide. Our field investigations coupled with laboratory incubations demonstrated that the microbial degradation potential of 17ß-estradiol (E2) with estrone as the intermediate was primarily driven by increased dissolved organic matter (DOM) in the water column of a cyanobacterial bloom. To explain the intrinsic contribution of cyanobacterial-derived DOM (C-DOM) to estrogen biodegradation, a combination of methods including bioassay, ultrahigh-resolution mass spectrometry, and microbial ecology were applied. The results showed that preferential assimilation of highly biodegradable structures, including protein-, carbohydrate-, and unsaturated hydrocarbon-like molecules sustained bacterial growth, selected for more diverse microbes, and resulted in greater estrogen biodegradation compared to less biodegradable molecules (lignin- and tannin-like molecules). The biodegradability of C-DOM decreased from 78% to 1%, whereas the E2 biodegradation rate decreased dramatically at first, then increased with the accumulation of recalcitrant, bio-produced lipid-like molecules in C-DOM. This change was linked to alternative substrate-induced selection of the bacterial community under highly refractory conditions, as suggested by the greater biomass-normalized E2 biodegradation rate after a 24-h lag phase. In addition to the increased frequency of potential degraders, such as Sphingobacterium, the network analysis revealed that C-DOM molecules distributed in high H/C (protein- and lipid-like molecules) were the main drivers structuring the bacterial community, inducing strong deterministic selection of the community assemblage and upregulating the metabolic capacity for contaminants. These findings provide strong evidence that estrogen biodegradation in eutrophic water may be facilitated by cyanobacterial blooms and provide a theoretical basis for ecological remediation of estrogen pollution.