In human languages, it is a common phenomenon for a single word to have multiple meanings. This study used fMRI to investigate how the brain processed different types of lexical ambiguity, and how it differentiated the meanings of ambiguous words. We focused on homonyms and polysemy that differed in the relatedness among multiple meanings. Participants (N = 35) performed a prime-target semantic relatedness task, where a specific meaning of an ambiguous word was primed. Results showed that homonyms elicited greater activation in bilateral dorsal prefrontal and posterior parietal cortices than polysemous words, suggesting that these regions may be more engaged in cognitive control when the meanings of ambiguous words are unrelated. Multivariate pattern analysis further revealed that meanings of homonyms with different syntactic categories were represented differently in the frontal and temporal cortices. The findings highlighted the importance of semantic relations and grammatical factors in the brain's representation of lexical ambiguities.