Numerous epidemiological studies have shown that male patients with uric acid nephrolithiasis outnumber female patients. To our knowledge, no research exists evaluating the reasons gender affects the development of uric acid nephrolithiasis. We hereby used a novel application of structural equation modeling to analyze the mediators of the effects of gender on uric acid nephrolithiasis. In 1,098 patients with nephrolithiasis between 2012 and 2016, male gender was found to have a statistically significant positive indirect effect on the development of uric acid nephrolithiasis, which was mediated by lower urine pH (estimate: 0.010, standard error: 0.005, critical ratio: 2.135, 95% confidence interval: 0.002-0.023, P = 0.017), lower estimated glomerular filtration rate (estimate: 0.014, standard error: 0.005, critical ratio: 2.993, 95% confidence interval: 0.006-0.025, P < 0.001), and higher incidence rate of gout (estimate: 0.009, standard error: 0.005, critical ratio: 2.028, 95% confidence interval: 0.002-0.021, P = 0.009). We conclude that low urine pH, impaired renal function, and gout are the mediators of the effect of male gender on the development of uric acid nephrolithiasis. The survey, treatment, and follow-up of kidney diseases, acidic urine, and uric acid metabolism disorders should be considered in men with uric acid nephrolithiasis.