Background/Objectives: Eravacycline is a fluorocycline with activity against multidrug-resistant (MDR) and difficult-to-treat (DTR) pathogens, but real-world outcome data are lacking for the treatment of infections caused by these organisms. The objective of this study was to evaluate the efficacy and safety of eravacycline for infections caused by MDR and/or DTR organisms. Methods: This was a retrospective, observational study of adult patients receiving eravacycline for at least 72 hours for MDR or DTR organisms. The primary outcome was 30-day mortality. Secondary outcomes included 60-day relapse, 30-day readmission, and adverse drug events (ADEs). Results: A total of 17 patients were included in the analysis. The cohort had a high baseline mortality risk (median Charlson Comorbidity Index of 5). Osteoarticular infections were the most common indication (52.9%). The most frequently isolated pathogens were Enterococcus spp. and Enterobacterales spp. (58.9% each). Most infections were polymicrobial. Eravacycline minimum inhibitory concentrations (MIC) were available in only 47% of cases, and the median time to treatment initiation was 6 days after culture collection. Thirty-day all-cause mortality occurred in 17.6% of patients. Among survivors, 60-day relapse and 30-day readmission were low (6% each). The ADEs occurred in 35% of patients but led to no discontinuations. Conclusions: In this cohort of severely ill patients with complex, predominantly polymicrobial MDR and DTR infections, eravacycline demonstrated favorable safety and efficacy results despite delays from index culture to initiation of targeted therapy. These data suggest eravacycline may be a viable treatment option for infections caused by MDR and DTR organisms.