The widespread use of antibiotics is a primary risk factor for the development of Clostridioides difficile infection (CDI), a major public health threat. In the United States (U.S.), a significant portion of antibiotics are prescribed in both the inpatient and outpatient settings. Despite efforts taken by the U.S. government and the Centers for Disease Control and Prevention (CDC) in decreasing the overall incidence of inappropriate antibiotic prescribing, these rates have not significantly changed over the past few years. While antibiotic prescribing rates have been described in the overall U.S. population, it is imperative to understand and characterize specific patient populations that are vulnerable to inappropriate antibiotic use. As antibiotics target the offending pathogens causing disease, they may also deplete important commensal bacteria that reside in the gut. Antibiotic use and overprescribing can further damage the gut microbiome, which can lead to the colonization of opportunistic pathogens like C. difficile and further, CDI. Few studies have evaluated the extent of CDI and its related outcomes in different racial/ethnic populations, as well as sex and age. Using the National Ambulatory Medical Care Survey (NAMCS), Veteran’s Health Administration (VHA), and Premier Healthcare Database (PHD), this study discovered national disparities in 1) overall and inappropriate antibiotic prescribing, 2) individual and combined antibiotic-associated CDI risk, and 3) CDI-associated health outcomes among patients of differing races/ethnicities, sex, and age groups. This study found that overall and inappropriate antibiotic prescribing rates were significant within all populations of interest. Additionally, this study showed that broad-spectrum antibiotics, like carbapenems, 3ʳᵈ, 4ᵗʰ, and 5ᵗʰ generation cephalosporins, and clindamycin, were significant risk factors for CDI. Combinations including fluoroquinolones were also shown to be significant risk factors for antibiotic CDI across all populations of interest. Lastly, patients 18 to 64 years and those 65 years and older were also shown to be significant predictors of CDI recurrence, while the same age groups and male sex were significant predictors of mortality. Findings from these analyses indicate that future studies in antibiotic and CDI-associated health disparities are needed to improve overall antimicrobial stewardship and patient outcomes.