Population-based estimates of the impact of gender throughout the whole course of brain metastases (BMs) at the time of diagnosis of systemic malignancies are insufficient. We aimed to discover the influence of gender on the presence of BMs in newly diagnosed malignancies and the survival of those patients on a population-based level.Midlife patients (40 years ≤ age ≤60 years) with newly diagnosed malignancies and BMs at the time of diagnosis were abstracted from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. Clinical variables adjusted patient data. The LASSO regression was performed to exclude the possibility of collinearity. Univariable and multivariable logistic regression analyses were applied to find independent predictors for the presence of BMs, while univariable and multivariable Cox proportional hazard regression analyses were used to determine prognosticators of survival. K-M curves were used to perform the survival analysis.276,327 population-based samples met inclusion criteria between 2014 and 2016, and 5747 (2.08%) patients were diagnosed with BMs at the time of diagnosis of systematic malignancies. Among all midlife patients with cancer, 44.02% (121,634) were male, while 51.68% (2970) were male among patients with BMs at the time of diagnosis. The most frequent tumor type was breast cancer (23.11%), and lung cancer had the highest incidence proportion of BMs among the entire cohort (19.34%). The multivariable logistic regression model suggested that female (vs. male, odds ratio [OR] 1.07, 95% CI: 1.01-1.14, p < 0.001) was associated with a higher risk of the presence of BMs at the time of diagnosis. Moreover, in the multivariable Cox model for all-cause mortality in individuals with BMs at diagnosis, female (vs. male, hazard ratio [HR], 0.86, 95% CI, 0.80-0.92, p < 0.001) was shown to have a lower risk of decreased all-cause mortality.The middle-aged females were at increased risk of developing BMs, while the middle-aged males with BMs were at higher risk of having poorer survival.© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.