Background <p>Traditional neuromodulation strategies show promise in enhancing cognitive abilities in bipolar disorder (BD) but remain suboptimal. This study introduces a novel multimodal neurostimulation (MNS) protocol to improve therapeutic outcomes.</p> Methods <p>The novel MNS protocol used individualized diffusion tensor imaging (DTI) data to identify fiber tracts between the dorsolateral prefrontal cortex and dorsal&#xa0;anterior cingulate cortex. The highest structural connectivity point is selected as the individualized stimulation site, which is then targeted using a combination of optimized transcranial alternating current stimulation (tACS) and robot-assisted navigated repetitive transcranial magnetic stimulation (rTMS). A double-blind randomized controlled trial was conducted to investigate the clinical efficacy of this innovative neuromodulation approach on cognitive abilities in stable-phase BD patients. One hundred BD patients were randomly assigned to four groups: group A (active tACS-active rTMS (MNS protocol)), group B (sham tACS-active rTMS), group C (active tACS-sham rTMS), and group D (sham tACS-sham rTMS). Participants underwent 15 sessions over 3&#xa0;weeks. Cognitive assessments (THINC integrated tool) were conducted at baseline (week 0) and post-treatment (week 3).</p> Results <p>Sixty-six participants completed all 15 sessions. Group A (MNS protocol) showed superior improvements in Spotter CRT, TMT, and DSST scores compared to other groups at week 3. Only group A exhibited significant activation in the left frontal region post-MNS intervention. The novel MNS protocol was well tolerated, with no significant side effects observed.</p> Conclusions <p>The study indicates that DTI-guided multimodal neurostimulation mode significantly improves cognitive impairments and is safe for stable-phase BD patients.</p> Trial registration <p>ClinicalTrials.gov identifier: NCT05964777.</p>