Well-designed randomized controlled trials (RCTs) have demonstrated safe and effective use of oral antimicrobial therapy for bone and joint infections. Application of data for implementation into real-world practice, however, has inherent challenges. This retrospective cohort study compared real-world use of intravenous versus oral antimicrobial therapy in bone and joint infections within a large healthcare system comprising both academic and community medical centers. The primary outcome was the proportion of treatment failure. Key secondary outcomes included the proportion of patients with logistical failure and risk factors associated with treatment and logistical failure. Among 166 patients included, 136 (82%) and 30 (18%) received predominantly intravenous and oral antimicrobial therapy, respectively. Treatment failure occurred in (77/121) 64% versus (18/25) 72% of patients in the intravenous and oral antimicrobial groups (p = 0.491; OR, 1.38; 95% CI, 0.56–3.33). Logistical failure occurred in 29% versus 47% of patients in the intravenous and oral antimicrobial groups (p = 0.150; OR, 1.93; 95% CI 0.79–4.70). Risk factors for treatment failure included peripheral vascular disease (OR, 2.61; 95% CI 1.02–7.80) and higher Charlson Comorbidity Index scores (OR, 1.18; 95% CI 1.04–1.36). Similar to previously published RCTs, treatment failure appeared comparable between groups; however, oral antimicrobial therapy was overall underutilized.