Objective: To explore the prognostic value of Ki-67 and p53 in patients with head and neck mucosal melanoma by analyzing the relevant data from previous patients. Methods: Data on Ki-67 and p53 immunohistochemical staining in 128 patients treated in Beijing Tongren Hospital between April 2005 and January 2021 were analyzed retrospectively. The correlation of Ki-67 and p53 expression with general clinical features and survival prognosis was analyzed. Results: Median follow-up time was 21 months. There were 66 cases in the group with Ki-67 < 40% and 62 cases in the group with Ki-67 > 40%, with 60 cases in the p53-negative group and 68 cases in the p53-positive group. Of the 128 patients, 67 died and 61 survived. There were 63 patients with distant metastasis and 33 patients with local recurrence. Ki-67 expression was related to distant metastasis but this was not an independent risk factor; however, it was an independent risk factor affecting the survival of patients. The survival time for patients with Ki-67 > 40% was significantly shorter than for patients with Ki-67 < 40%. P53 expression had no significant effect on survival and prognosis. Conclusion: Ki-67 is related to the disease stage and overall survival of patients with head and neck mucosal melanoma. It may have a guiding significance for the prognosis of patients as those with higher Ki-67 levels had poorer prognosis. However, the incidence rate of this disease is low, and all of the results need to be verified with a larger dataset.