Background: Native joint septic arthritis is a severe infection associated with considerable morbidity. The data about the microbiological spectrum, treatment methods, and long-term outcomes are heterogeneous. Methods: We performed a decade-long retrospective study encompassing all patients with native joint septic arthritis treated at our institution, a tertiary orthopedic center. Data on demographics, clinical parameters, microbiology, surgical interventions, and antibiotic use were gathered. Outcomes included reoperation, persistent infection and mortality during follow-up. We used logistic regression to identify predictors of adverse outcomes, and Kaplan–Meier analyses to evaluate reoperation-free survival among microbiologic groups. Results: A total of 114 patients (103 adults and 11 children) were included. Cultures yielded positive results in 72 out of 103 (70%) adults and 8 out of 11 (73%) children. Staphylococcus aureus was the primary pathogen in adults (49% of positives) and children (88%), followed by coagulase-negative staphylococci. Antibiotics were administered to all patients, with combinations of at least two molecules in 68% of adults and 91% of children, while surgical intervention predominantly consisted of debridement alone. In adults, an elevated preoperative white blood cell count was associated with unfavorable outcomes in univariate analysis (odds ratio 1.14, 95% confidence interval 1.01–1.30, p = 0.040). The Kaplan–Meier analysis revealed no significant differences in reoperation-free survival across microbiologic groups (log-rank p = 0.361). Conclusions: Over a ten-year period, Staphylococcus aureus remained the predominant cause of native joint septic arthritis; however, culture-negative cases and coagulase-negative staphylococci were also common. Only preoperative leukocytosis was a predictor of poor outcomes, while microbiologic etiology did not significantly influence the risk of reoperation, potentially indicating early and effective therapy. These findings highlight the intricacy of native joint septic arthritis and the necessity for enhanced diagnostics and prognostic stratification.