Semantically ambiguous words challenge speech comprehension, particularly when listeners must select a less frequent (subordinate) meaning at disambiguation. Using combined magnetoencephalography (MEG) and EEG, we measured neural responses associated with distinct cognitive operations during semantic ambiguity resolution in spoken sentences: (i) initial activation and selection of meanings in response to an ambiguous word and (ii) sentence reinterpretation in response to subsequent disambiguation to a subordinate meaning. Ambiguous words elicited an increased neural response approximately 400–800 msec after their acoustic offset compared with unambiguous control words in left frontotemporal MEG sensors, corresponding to sources in bilateral frontotemporal brain regions. This response may reflect increased demands on processes by which multiple alternative meanings are activated and maintained until later selection. Disambiguating words heard after an ambiguous word were associated with marginally increased neural activity over bilateral temporal MEG sensors and a central cluster of EEG electrodes, which localized to similar bilateral frontal and left temporal regions. This later neural response may reflect effortful semantic integration or elicitation of prediction errors that guide reinterpretation of previously selected word meanings. Across participants, the amplitude of the ambiguity response showed a marginal positive correlation with comprehension scores, suggesting that sentence comprehension benefits from additional processing around the time of an ambiguous word. Better comprehenders may have increased availability of subordinate meanings, perhaps due to higher quality lexical representations and reflected in a positive correlation between vocabulary size and comprehension success.