Spinal osteomyelitis and spondylodiscitis (SD) are infections of the vertebral body and disc, respectively, with more than 50% associated with Staphylococcus aureus. Methicillin-resistant S. aureus (MRSA) has become a pathogen of interest in cases of SD due to increasing prevalence. The purpose of this investigation was to characterize the current epidemiological and microbiological landscape in SD cases, in addition to medical and surgical challenges in treating these infections. The PearlDiver Mariner database was queried for ICD-10 codes to identify cases of SD from 2015 to 2021. The initial cohort was stratified by offending pathogens, including methicillin-sensitive S. aureus (MSSA) and MRSA. Primary outcome measures included epidemiological trends, demographics, and rates of surgical management. Secondary outcomes included length of hospital stay, rate of reoperation, and complications associated with surgical cases. Multivariable logistic regression was used to control for age, gender, region, and Charlson Comorbidity Index (CCI). Nine thousand nine hundred eighty-three patients met the inclusion criteria and were retained for this study. Approximately half (45.5%) of SD cases resulting from S. aureus infections each year were resistant to beta-lactam antibiotics. The proportion of cases that were managed surgically was 31.02%. Among the cases that involved surgical intervention, 21.83% underwent revision operations within 30 days of the original procedure and 37.29% of cases returned to the operating room within 1 year. Substance abuse, specifically alcohol, tobacco, and drug use, were strong predictors for surgical intervention in cases of SD (all p < 0.001), in addition to obesity (p = 0.002), liver disease (p < 0.001), and valvular disease (p = 0.025). After adjusting for age, gender, region, and CCI, cases of MRSA were more likely to undergo surgical management (OR 1.19, p = 0.003). MRSA SD also exhibited higher rates of reoperation within 6 months (OR 1.29, p = 0.001) and 1 year (OR 1.36, p < 0.001). Surgical cases resulting from MRSA infections also exhibited higher morbidity and significant rates of transfusion (OR 1.47, p = 0.030), acute kidney injury (OR 1.35, p = 0.001), pulmonary embolism (OR 1.44, p = 0.030), pneumonia (OR 1.49, p = 0.002), and urinary tract infection (OR 1.45, p = 0.002) compared with MSSA SD infections. More than 45% of cases of S. aureus SD in the US are resistant to beta-lactam antibiotics, presenting obstacles in treatment. Cases of MRSA SD are more likely to be managed surgically and have higher rates of complications and reoperations. Early detection and prompt operative management are imperative to reduce the risk of complications.