Objective: A meta-analysis was performed to compare mold-active triazoles or lipid amphotericin B plus an echinocandin to non-echinocandin monotherapy for acute invasive aspergillosis (IA). Methods: We searched PubMed, EMBASE, and other databases through May 2013 unrestricted by language. We included observational and experimental studies wherein patients with proven or probable IA by EORTC/MSG criteria underwent our comparative intervention. PRISMA and MOOSE guidelines were followed and quality was assessed using the Jadad and Newcastle–Ottawa criteria. Meta-regression with fixed and random effects and sensitivity analyses were performed. The primary study outcome measure was 12-week overall mortality. The secondary outcome assessed was complete and partial response. Results: Only observational studies of primary 12-week survival showed heterogeneity (I2 = 48.96%, p = 0.05). For salvage IA therapy, fixed effects models demonstrated improved 12-week survival (Peto odds ratio (OR) 1.80, 95% confidence interval (CI) 1.08–3.01) and success (Peto OR 2.17, 95% CI 1.21–3.91) of combination therapy. Significance remained after applying random effects as a sensitivity analysis (12-week survival: Peto OR 1.90, 95% CI 1.04–3.46, and unchanged value for success). Restriction to high quality studies and including echinocandins as the comparator for refractory IA revealed an adjusted OR of 1.72 (95% CI 0.96–3.09; p = 0.07) for global success, while the survival endpoint remained unaltered. Conclusions: Combination antifungals for IA demonstrate improved outcomes over monotherapy in the salvage setting. Clinicians should consider this approach in certain situations.