Rationale & Objective: Animal models of kidney disease suggest a protective role for female sex hormones, but some authorities assert that female sex in humans is a risk factor for acute kidney injury (AKI). To better understand the risk of AKI, we studied the strength of association between sex and AKI incidence in hormonally distinct age groups across the life span. Study Design: Prospective cohort study. Setting & Participants: All patients hospitalized in the Montefiore Health System between October 15, 2015, and January 1, 2019, excluding those with kidney failure or obstetrics diagnoses. Exposure: Male versus female sex. Outcome: AKI occurring during hospitalization based on KDIGO definitions. Analytical Approach: Generalized estimating equation logistic regression adjusted for comorbidities, sociodemographic factors, and severity of illness. Analyses were stratified into 3 age categories: 6 months to ≤16 years, >16 years to <55 years, and ≥55 years. Results: A total of 132,667 individuals were hospitalized a total of 235,629 times. The mean age was 55.2 ± 23.8 (SD) years. The count of hospitalizations for women was 129,912 (55%). Hospitalization count among Black and Hispanic patients was 71,834 (30.5%) and 24,199 (10.3%), respectively. AKI occurred in 53,926 (22.9%) hospitalizations. In adjusted models, there was a significant interaction between age and sex (P < 0.001). Boys and men had a higher risk of AKI across all age groups, an association more pronounced in the age group >16 years to <55 years in which the odds ratio for men was 1.7 (95% CI, 1.6-1.8). This age-based pattern remained consistent across prespecified types of hospitalizations. In a sensitivity analysis, women older than 55 years who received prescriptions for estrogen had lower odds of AKI than those without prescriptions. Limitations: Residual confounding. Conclusions: The greatest relative risk of AKI for males occurred during ages >16 to <55 years. The lower risk among postmenopausal women receiving supplemental estrogen supports a protective role for female sex hormones. Plain-Language Summary: Male sex is a risk factor for acute kidney injury (AKI) in animals, but in human studies this association is not as robust. We studied hospitalizations at a single center to examine the association of hospital-acquired AKI and sex. After controlling for various sources of potential bias and stratifying by age categories through the life course, we observed that men have a higher risk of AKI throughout life. This risk was especially high compared with women of fertile age and older women prescribed estrogen. This pattern was consistent in prespecified subgroups of hospitalizations. These results support a protective role for female sex hormones in the occurrence of hospitalized AKI.