To contribute to the understanding of joined factors in the environment, impact of pure microcystins (-RR and -LF) on zebra fish (Danio rerio) embryos were investigated individually and in combination with a natural organic matter (NOM). The applied NOM was a reverse osmosis isolate from Lake Schwarzer See (i.e., Black Lake, BL-NOM). Teratogenic effects were evaluated through changes in embryonic development within 48 h of exposure. Detoxication activities were assessed by the activities of phase II biotransformation enzymes, soluble and microsomal glutathione S-transferase (s, mGST). Oxidative stress was assessed by determining both the production of hydrogen peroxide and by analyzing the activities of the antioxidative enzymes, guajacol peroxidase (POD), catalase (CAT), glutathione peroxidase (GPx), and the glutathione restoring enzyme glutathione reductase (GR). Energetic costs were evaluated by determining contents of fat, carbohydrates, and proteins in both exposed and control embryos. BL-NOM attenuated toxic effects of MC-LF and MC-RR verified by less pronounced teratological effects within 24 h, in particular, as well as less rise in the activity of s-GST, when compared with embryos exposed to either pure toxins or in combination with organic matter. BL-NOM also diminished oxidative effects caused by MC-LF; however, it failed to attenuate oxidative stress caused by MC-RR. Content of lipids was significantly reduced in exposed embryos following a trend similar to that obtained with teratological and enzymatic assays confirming the attenuating effect of BL-NOM. Physiological responses to microcystins and NOM required energetic costs, which were compensated to the expense of the energy resources of the yolk, which in turn might affect the normal development of embryos.