An important and unresolved question is how the human brain processes speech for meaning after initial analyses in early auditory cortical regions. A variety of left-hemispheric areas have been identified that clearly support semantic processing, although a systematic analysis of directed interactions among these areas is lacking. We applied dynamic causal modeling of functional magnetic resonance imaging responses and Bayesian model selection to investigate, for the first time, experimentally induced changes in coupling among three key multimodal regions that were activated by intelligible speech: the posterior and anterior superior temporal sulcus (pSTS and aSTS, respectively) and pars orbitalis (POrb) of the inferior frontal gyrus. We tested 216 different dynamic causal models and found that the best model was a “forward” system that was driven by auditory inputs into the pSTS, with forward connections from the pSTS to both the aSTS and the POrb that increased considerably in strength (by 76 and 150%, respectively) when subjects listened to intelligible speech. Task-related, directional effects can now be incorporated into models of speech comprehension.