Objective To explore the levels and diagnostic value of serum microRNA-124 （miR-124） and microRNA-381 （miR-381） in first-episode schizophrenia patients. Methods A total of 91 first-episode schizophrenia patients admitted to Chongqing Mental Health Center from May 2019 to May 2021 were regarded as the first-episode schizophrenia group. Another 70 volunteers who came to our hospital for health examinations during the same period were regarded as the control group. RT-qPCR was applied to detect serum levels of miR- 124 and miR-381. Positive and Negative Symptom Scale （PANSS） was applied to assess the patients' condition in first-episode ES group. According to the scores， the patients were divided into mild group （n=38）， moderate group （n=29）， and severe group （n=24）. Spearman method was applied to analyze the correlation between levels of serum miR-124， miR-381 and PANSS scores in first-episode schizophrenia patients. Binomial Logistic regression was used to analyze the influencing factors of the onset in first-episode schizophrenia patients. Receiver operating characteristic （ROC） curve was applied to analyze the diagnostic value of levels of serum miR-124 and miR-381 for severe first-episode schizophrenia. Results The level of serum miR-124 in the first-episode schizophrenia group was obviously lower than that in the control group， while miR-381 was obviously higher than that in the control group， and the differences were statistically significant （t=7.022， 11.192； P＜ 0.01）. Compared with the mild group， the level of serum miR-124 in the moderate group and severe group were obviously reduced， while the level of miR-381 was obviously increased， with statistical significance （P＜ 0.05）. Compared with the moderate group， the severe group showed an obvious decrease in the level of serum miR-124， and an obvious increase in the level of miR-381， with statistical significance （P＜0.05）. The scores of positive symptom， negative symptom， depression emotion， excitement， cognitive function and the total score of PANSS were negatively correlated to the level of serum miR-124 （P＜ 0.05）， and positively correlated to level of serum miR-381 （P＜ 0.05）. miR-381 was a risk factor for first-episode schizophrenia （OR=0.682， 95%CI=0.511 to 0.910， P＜0.05）， while miR-124 was a protective factor （OR=2.248， 95%CI=1.125 to 4.490， P＜0.05）. The AUC of serum miR-124， miR-381， and their combination in the diagnosis of severe first-episode schizophrenia was 0.877， 0.781， and 0.935， respectively. The sensitivity of combined diagnosis was 95.83%， and the specificity was 82.09%. The combination of the two was superior to the individual diagnosis of serum miR-124 and miR-381 （Zcombination-miR-124=2.197， Pcombination-miR-124=0.028； Zcombination-miR-381=2.927， Pcombination-miR-381=0.003）. Conclusions The serum miR-124 level in first-episode schizophrenia patients is low and negatively correlated with the severity of the condition. The serum miR-381 level is high and positively correlated with the severity of the condition. Serum levels of miR-124 and miR-381 can be used as markers for diagnosing severe first-episode schizophrenia and determining the severity of the condition.