People with schizophrenia often show impairments in cognitive flexibility, which is a key aspect of executive function, and this contributes to poor functional outcomes. Neuroimaging studies in schizophrenia have implicated dysfunction within the dorsomedial striatum (DMS), which is a subcortical brain region integral to reversal learning, i.e., a form of cognitive flexibility involving adapting behaviour in response to changing reward contingencies. Given its integral role in these processes, understanding the biological and cognitive consequences related to DMS dysfunction may inform therapeutic strategies to mitigate cognitive inflexibility. This study employed a serial reversal learning paradigm to examine decision-making under probabilistic uncertainty and investigated the effects of DREAADs-based chemogenetic inhibition of the DMS on performance and the subsequent activity of corticostriatal circuitry in male C57BL/6J mice. Inhibition of DMS activity impaired reversal learning under probabilistic uncertainty, specifically disrupting reward-based decision-making strategies such as by reducing win-stay behaviour. Furthermore, DMS inactivation led to diminished corticostriatal network co-activation during reversal learning, with pronounced reductions in the efficiency of anterior cingulate, orbitofrontal, and insular cortices—cortical regions crucial for flexible learning. These results suggest that inhibiting DMS function disrupts behavioural adaptation as well as corticostriatal co-activation, a mechanism that potentially contributes to the cognitive inflexibility observed in schizophrenia. By elucidating the neural substrates of reversal learning deficits, this study provides insights into the mechanisms by which DMS inhibition affects cognitive flexibility and highlights potential targets for therapeutic intervention in schizophrenia-relevant cognitive impairments.