To explore the relationship of p53 gene mutation with clinical features and prognosis of myeloproliferative neoplasms (MPN). Methods Totally 126 patients with MPN admitted to the hospital were selected from January 2017 to January 2020. p53 gene mutation was detected by second generation sequencing. The patients were followed up to count the overall survival time and cumulative survival rate. The influence of p53 gene mutation on the patients' clinical features and prognosis was analyzed. Results A total of 12 (9.52%) patients with p53 gene mutations were detected in this study, and the mutations were mainly located in exons 4-8. There was no statistically significant difference in the detection rate of p53 gene mutations in different types of patients (P＞0.05). Patients in the p53 mutation group were older than those in the non-p53 mutation group, and the WBC was lower than that in the non-p53 mutation group (P＜0.05). The chromosomal karyotypes and IPSS stratification showed statistically significant differences between the two groups (P＜0.05). The OS time and cumulative survival rate of the non-p53 mutation group were significantlylonger/higher than those of the p53 mutation group (P＜0.05). Conclusion The incidence of p53 gene mutations in patients with MPN is relatively higher, which is related to the patient's age, WBC, abnormal karyotypes and IPSS stratification. p53 gene mutations can affect the prognosis of patients, which indicates that it can be used as an objective indicator to screen highrisk population of poor prognosis.