Although schizophrenia is considered a brain disorder, the role of brain organization for symptomatic improvement remains inadequately defined. We investigated the relationship between baseline brain morphology, resting-state network connectivity and clinical response after 24-weeks of antipsychotic treatment in patients with schizophrenia (n = 95) using integrated multivariate analyses. There was no significant association between clinical response and measures of cortical thickness (r = 0.37, p = 0.98) and subcortical volume (r = 0.56, p = 0.15). By contrast, we identified a strong mode of covariation linking functional network connectivity to clinical response (r = 0.70; p = 0.04), and particularly to improvement in positive (weight = 0.62) and anxious/depressive symptoms (weight = 0.49). Higher internal cohesiveness of the default mode network was the single most important positive predictor. Key negative predictors involved the functional cohesiveness of central executive subnetworks anchored in the frontoparietal cortices and subcortical regions (including the thalamus and striatum) and the inter-network integration between the default mode and sensorimotor networks. The present findings establish links between clinical response and the functional organization of brain networks involved both in perception and in spontaneous and goal-directed cognition, thereby advancing our understanding of the pathophysiology of schizophrenia.