Background: Few studies have examined the epidemiology of polypharmacy in non-institutionalized elderly adults with regard to sex differences. This study aimed to identify the prevalence of polypharmacy among people ≥65years old residing in Spain, analyze trends in that prevalence from 2011/12 to 2020, describe the use of the medicines involved and study the possible relationship between polypharmacy and certain sociodemographic, health-related variables, as well as the use of care services by sex. Methods: A nationwide cross-sectional study with 21,841 non-institutionalized people ≥65years old from the Spanish National Health Survey (2011/2012 and 2017) and the European Health Survey in Spain (2014 and 2020) was performed. We used descriptive statistics, performing two binary logistic regressions to determine the factors related to polypharmacy. Results: The prevalence of polypharmacy was 23.2% (women: 28.1%, men: 17.2%; p < 0.001). The most commonly consumed medicines were analgesics and tranquillizers, relaxants or sleeping pills in elderly women, compared with antihypertensives, antacids and antiulcer drugs and statins for elderly men. In both sexs, the positive predictors of polypharmacy included average, poor and very poor self-perceived states of health, people with overweight and obesity, being severely/non-severely limited due to a health problem, having ≥ three chronic conditions, visits to the family doctor and hospitalization. Among elderly women, negative predictors were alcohol intake, whereas in elderly men positive predictors were being 75-84years old, being current smokers and having 1, 2 chronic conditions. Conclusion: Polypharmacy has a prevalence of 23.2%, with women accounting for 28.1% and men 17.2% of the total. Knowledge of positive and negative predictors of polypharmacy have important implications for public health efforts to develop or improve health guidelines and strategies for promoting the proper use of medication, particularly in the elderly population by sex.