BACKGROUND: Managing Cancer and Living Meaningfully (CALM) intervention's impact on chemotherapy-related cognitive impairment (CRCI) in breast cancer survivors (BCs) was investigated through resting-state functional magnetic resonance imaging (rs-fMRI) to elucidate the underlying neural mechanisms involved. METHODS: 68 BCs were randomly assigned to either the CALM group (33 patients) or the care-as-usual (CAU) group (35 patients). Cognitive function was assessed before and after the intervention in both groups using the Mini Mental State Examination (MMSE) scale. Pre- and post-intervention rs-fMRI data were also collected for regional homogeneity (ReHo) and functional connectivity (FC) analyses in the CALM group. A total of 68 BCs were randomly assigned to either the CALM group (n = 33) or the care-as-usual (CAU) group (n = 35). Cognitive function was evaluated pre- and post-intervention using the Mini-Mental State Examination (MMSE). In the CALM group, rs-fMRI data were acquired before and after the intervention to assess alterations in regional homogeneity (ReHo) and functional connectivity (FC). RESULTS: CALM intervention demonstrated a greater enhancement in cognitive function compared to CAU ( = 0.004). Following CALM, ReHo exhibited an increase in bilateral occipital and temporal regions, including the superior, middle, and inferior occipital gyri, lingual gyrus, as well as the middle and superior temporal gyri, while a decrease was observed in frontal and cingulate regions, including the bilateral middle, medial, and dorsolateral superior frontal gyri, anterior cingulate and paracingulate gyri, precuneus, posterior cingulate, and left angular gyrus. FC analysis revealed diminished connectivity between the middle frontal gyrus and occipital/calcarine regions, whereas connectivity strengthened with the left anterior cingulate/paracingulate and right orbital frontal regions. ΔMMSE exhibited a positive correlation with ReHo in the left middle frontal gyrus ( = 0.355, = 0.042) and a reduction in middle frontal-occipital FC (left calcarine: = 0.353, = 0.044; right/left middle occipital: = 0.388/0.423, = 0.029/0.014). CONCLUSION: CALM intervention mitigates CRCI in BCs, with the middle frontal gyrus may play a critical.