Purpose Negative emotions, as an important risk factor, promote the development of many diseases. The study is designed to discuss alterations of interhemispheric functional connectivity (FC) with congenital blindness (CB) subjects by adopting voxel-mirrored homotopic connectivity (VMHC). Based on the alterations in FC, we assessed whether there was an interaction between blindness and emotional regulation. Method VMHC values were collected from 24(males/females = 9/15) subjects with congenital blindness and 24(males/females = 9/15) healthy controls. The gender, age and other information of the healthy controls were closely matched with the disease group. The VMHC values were applied to assess alterations in hemispheric FC between the two groups. Receiver Operating Characteristic (ROC) were applied so as to classify the mean VMHC values of the CB and HC subjects. In addition, an evaluation, which was applied the Pearson Correlation analysis, was employed to compare the correlation between VMHC values of specific brain areas and clinical features of CB subjects. Result The area under curve (AUC) was 0.8750 (P < 0.0001) for bilateral fusiform gyrus (FFG), 0.9670 (P < 0.0001) for bilateral superior occipital gyrus (SOG), 0.9653 (P < 0.0001) for bilateral thalamus (THA) and 0.9462 (P < 0.0001) for bilateral paracentral lobule (PCL). Furthermore, anxiety scores (AS) and depression scores (DS) displayed a positive correlation with the VMHC values of bilateral thalamus (r =− 0.943; P< 0.001 and r = 0.869; P< 0.001) in CB group. Conclusion In the CB group, aberrant interhemispheric FC was observed in specific cerebral regions. These altered VMHC values in the cerebral areas might be potential diagnostic markers of emotional disorders and aberrant brain activities in the CB patients. Humanistic care and necessary psychological treatment for blind patients may be one of the measures to prevent vision from persistent loss in the future. At the same time, the changes of brain function may also provide new ideas for individualized treatment of patients with anxiety, depression and other emotional disorders.