•Mucormycosis-associated 90-day mortality remains high (41%) despite the advent of newer antifungals.•First-line antifungals with good efficacy and safety remain an urgent unmet need.•i.v. lipid-based AmB did not confer a survival advantage over i.v. C-AmB but was associated with fewer adverse effects.•Initial combination antifungal therapy was not associated with reduced mortality compared with initial AmB monotherapy.•Surgery is fundamental to improving survival and must be accessible to all patients. With the advent of newer antifungals, optimum treatment of mucormycosis remains to be fully elucidated. This study systematically evaluated the contemporary management and outcomes of mucormycosis. Mucormycosis cases in patients aged ≥18 years published between January 2000 and January 2017 were identified through Ovid MEDLINE and Embase. Of the 3619 articles identified, 600 (851 individual patient cases) were included in the review. Of the 851 patient cases, antifungal treatment details were available for 785. Intravenous (i.v.) amphotericin B formulations remained the most commonly prescribed first-line antifungals (760/785; 96.8%): 88.2% (670/760) were initiated as monotherapy and 11.8% (90/760) as combination antifungal therapy. Posaconazole oral suspension monotherapy was prescribed as an initial antifungal in 11 cases. It was also administered as maintenance or salvage therapy in 39 and 25 cases, respectively. Itraconazole capsule monotherapy (n = 10) was prescribed primarily for cutaneous disease in patients not receiving any immunosuppressive therapy. All-cause 90-day mortality was 41.0% (349/851). Initial treatment with combination antifungals did not reduce 90-day mortality compared with i.v. conventional amphotericin B or i.v. liposomal amphotericin B monotherapy 35/90 (38.9%) vs. 146/369 (39.6%) vs. 91/258 (35.3%), respectively; P = 0.541. Concomitant surgical and antifungal therapy was associated with significantly lower 90-day mortality compared with treatment with antifungals alone (OR = 0.23, 95% CI 0.13–0.41; P < 0.001). The findings suggest that first-line antifungals with good efficacy remain an urgent unmet need. Whilst surgery is fundamental to improving survival, the clinical utility of combination antifungal therapy or posaconazole monotherapy requires further investigation.