Tailored multidomain lifestyle modifications are recommended for reducing dementia risk in mild neurocognitive disorder (mNCD). However, evidence of their capacity to modify disease trajectories and restore functional brain abnormalities remains limited. We aimed to explore functional brain adaptations and correlate underlying cognitive improvements in response to a personalized “exergame as medicine” program (“Brain-IT”) for secondary mNCD prevention. Participants were randomized to 12 weeks home-based “Brain-IT” (physical-motor-cognitive with integrated biofeedback breathing training; 120 min/week, moderate intensity) + usual care or usual care alone. Resting-state functional connectivity at the seed(hippocampus)-to-voxel level and task-based full-factorial analysis of variance for functional activation (Blood Oxygenation Level Dependent signal responses) and their correlations with episodic memory performance were analyzed. Data from 32 mNCD participants (71.9 ± 8.1 years; 28% females) with mostly biomarker-supported Alzheimer’s etiology (57%) were analyzed. Key findings were significantly (p < 0.0001) reduced hippocampus hyperactivation during memory encoding (partial η2 = 0.19) and compensatory functional activation increases in the right precuneus (d = 0.76) and middle cingulate gyrus (d = 0.26) that correlated with memory retrieval accuracy changes—all in favor of “Brain-IT.” These exploratory findings are consistent with a potential short-term brain-protective role of personalized “exergame as medicine” therapy in mNCD that require confirmation in hypothesis-driven and adequately powered RCTs. Given the overlooked role of exergames in dementia prevention, hybrid implementation-effectiveness research with long-term follow-up measuring biomarker-related and clinical progression should evaluate whether potential brain-protective effects translate to delaying and/or preventing progression to dementia. Registration: https://clinicaltrials.gov/ct2/show/NCT05387057 (May 18, 2022)