Recent neuroimaging research has suggested that unequal cognitive efforts exist between interpreting from language 1 (L1) to language 2 (L2) compared with interpreting from L2 to L1. However, the neural substrates that underlie this directionality effect are not yet well understood. Whether directionality is modulated by interpreting expertise also remains unknown. In this study, we recruited two groups of Mandarin (L1)/English (L2) bilingual speakers with varying levels of interpreting expertise and asked them to perform interpreting and reading tasks. Functional near-infrared spectroscopy (fNIRS) was used to collect cortical brain data for participants during each task, using 68 channels that covered the prefrontal cortex and the bilateral perisylvian regions. The interpreting-related neuroimaging data was normalized by using both L1 and L2 reading tasks, to control the function of reading and vocalization respectively. Our findings revealed the directionality effect in both groups, with forward interpreting (from L1 to L2) produced more pronounced brain activity, when normalized for reading. We also found that directionality was modulated by interpreting expertise in both normalizations. For the group with relatively high expertise, the activated brain regions included the right Broca’s area and the left premotor and supplementary motor cortex; whereas for the group with relatively low expertise, the activated brain areas covered the superior temporal gyrus, the dorsolateral prefrontal cortex (DLPFC), the Broca’s area, and visual area 3 in the right hemisphere. These findings indicated that interpreting expertise modulated brain activation, possibly because of more developed cognitive skills associated with executive functions in experienced interpreters.