The Cognitive Bias (CogBIAS) hypothesis proposes that cognitive biases develop as a function of environmental influences (which determine the valence of biases) and the genetic susceptibility to those influences (which determines the potency of biases). The current study employed a longitudinal, polygenic-by-environment approach to examine the CogBIAS hypothesis. To this end, measures of life experiences and polygenic scores for depression were used to assess the development of memory and interpretation biases in a three-wave sample of adolescents (12–16 years) (N = 337). Using mixed effects modeling, three patterns were revealed. First, positive life experiences (PLEs) were found to diminish negative and enhance positive forms of memory and social interpretation biases. Second, and against expectation, negative life experiences and depression polygenic scores were not associated with any cognitive outcomes, upon adjusting for psychopathology. Finally, and most importantly, the interaction between high polygenic risk and greater PLEs was associated with a stronger positive interpretation bias for social situations. These results provide the first line of polygenic evidence in support of the CogBIAS hypothesis, but also extend this hypothesis by highlighting positive genetic and nuanced environmental influences on the development of cognitive biases across adolescence.