Phenotypic plasticity is the ability of an organism to show various phenotypes which is based on genetic basis and mostly influenced by environmental heterogeneity. Research has shown that a change in environmental conditions could alter the expression of traits during development (i.e., within-generational plasticity) as well as induce heritable phenotypic responses that persist for multiple generations (i.e., trans-generational plasticity). Cladoceran zooplankton often exhibit plasticity of inducible defenses in response to fish predation risks. Given that inducible defense may depend to a great extent on basic metabolic fitness of cladocerans, disrupting chemicals in homeostasis (e.g. antidepressant sertraline) may therefore modify the expression of inducible defense. Since sertraline has highly biological activity and longstanding persistent in water, together with short generation time of cladocerans, there is an urgent need to understand the influence by multigenerational exposure of sertraline on the within- and trans-generational inducible defense of cladocerans. The results showed that two-generational exposure of sertraline modified the predator-induced phenotypic plasticity within-generation, expressed as morphological enhancement of body-size reduction, relative-spine-length elongation found in predation-induced Daphnia pulex as opposed to predation-free animals. No predation-induced variation in D. pulex population fitness seemed to be associated with the sertraline exposure. Furthermore, we found that two-generational exposure of sertraline mediated the trans-generational inducible defense, expressed as enhanced morphological response but simultaneously a population fitness cost. Collectively, our results denote that although long-term exposure to sertraline has marginal mortality to zooplankton, it still negatively affects within- and trans-generational plasticity in the inducible defense of cladocerans as well as their population abundance and may consequently dull antipredation response involved in the structure and function of 'prey-predator' interaction.