Word learning plays a central role in language development and is a key predictor for later academic success. The underlying neural basis of successful word learning in children is still unknown. Here, we took advantage of the opportunity afforded by diffusion-weighted magnetic resonance imaging to investigate neural plasticity in the white matter of typically developing preschool children as they learn words. We demonstrate that after 3 weeks of word learning, children showed significantly larger increases of fractional anisotropy (FA) in the left precentral white matter compared to two control groups. Average training accuracy was correlated with FA change in the white matter underlying the left dorsal postcentral gyrus, with children who learned more slowly showing larger FA increases in this region. Moreover, we found that the status of white matter in the left middle temporal gyrus, assumed to support semantic processes, is predictive for early stages of word learning. Our findings provide the first evidence for white matter plasticity following word learning in preschool children. The present results on learning novel words in children point to a key involvement of the left fronto-parietal fiber connection, known to be implicated in top-down attention as well as working memory. While working memory and attention have been discussed to participate in word learning in children, our training study provides evidence that the neural structure supporting these cognitive processes plays a direct role in word learning.