Background: Given the increasing prevalence of dementia, any intervention that can effectively slow the deterioration of cognitive function is of great importance. Objective: This study investigated the efficacy of a human-computer interaction-based comprehensive cognitive training program in cognitively impaired elderly individuals living in a nursing home. Methods: All subjects, who were aged ≥70 years and had cognitive impairment, were randomly allocated to an intervention group (n = 19) or a control group (n = 14). The intervention group received human-computer interaction-based comprehensive cognitive training for 24 weeks. Neuropsychological examinations were conducted before and after this period. The intervention group was subdivided into two groups according to the scores of global cortical atrophy (GCA) to evaluate the impact of training effectiveness on GCA. Results: After 24 weeks, neither group showed a significant change compared with baseline cognitive examinations. However, there was a tendency for greater improvement in memory, language, and visuospatial abilities for the intervention group as compared with controls. Patients with mild cognitive impairment showed improvements in language and visuospatial capacity, while patients with dementia showed improvements in attention/orientation, memory, language, and fluency. However, none of these findings were statistically significant. The results for the intervention subgroups showed that visuospatial ability improvement was significantly greater among those with a global cortical atrophy score of ≤15 (p < 0.05). Conclusion: Human-computer interaction-based comprehensive training may improve cognitive functions among cognitively impaired elderly individuals. The training effect was most prominent among those with milder cerebral atrophy.