Background: Prior resting state functional Magnetic Resonance Imaging studies (rs-fMRI) via the regional homogeneity (ReHo) method have demonstrated inconsistent and conflicting results because of several confounding factors, such as small sample size, medicinal influence, and illness duration. Relationships between ReHo measures and cognitive impairments in patients with drug-naive First-Episode Schizophrenia (dn-FES) are rarely reported. This study was conducted to explore the correlations between ReHo measures and cognitive deficits and clinical symptoms in patients with dn-FES. Methods: A total of 69 patients with dn-FES and 74 healthy controls were recruited. MATRICS Consensus Cognitive Battery (MCCB), Wechsler Adult Intelligence Scale (WAIS), and Positive And Negative Syndrome Scale (PANSS) were used to assess cognitive function, Intelligence Quotient (IQ), and clinical symptoms, respectively. The correlations between ReHo maps and cognitive deficits and the severity of symptoms were examined using strict correlation analysis. Results: ReHo values in right Middle Frontal Gyrus (MFG) and Superior Frontal Gyrus (SFG) increased in dn-FES group, whereas ReHo values in right cuneus decreased. Correlation analysis showed that the ReHo values in right MFG positively correlated with attention/vigilance impairments, social cognition deficits, and the severity of clinical manifestations. Conclusions: These findings suggested that abnormal spontaneous activities in right MFG reflect illness severity and cognitive deficits, which also serve as a basis for establishing objective diagnostic markers and might be a clinical intervention target for treating patients with schizophrenia.