The rarity of mixed-phenotype acute leukemia (MPAL) has resulted in diffuse literature consisting of small case series, thus precluding a consensus treatment approach. We conducted a meta-analysis and systematic review to investigate the association of treatment type (acute lymphoblastic leukemia [ALL], acute myeloid leukemia [AML], or "hybrid" regimens), disease response, and survival. We searched seven databases from inception through June 2017 without age or language restriction. Included studies reported sufficient treatment detail for de novo MPAL classified according to the well-established European Group for Immunological Characterization of Acute Leukemias (EGIL) or World Health Organization (WHO2008) criteria. Meta-analyses and multivariable analyses of a patient-level compiled case series were performed for the endpoints of complete remission (CR) and overall survival (OS). We identified 97 reports from 33 countries meeting criteria, resulting in 1,499 unique patients with data, of whom 1,351 had sufficient detail for quantitative analysis of the study endpoints. Using either definition of MPAL, meta-analyses revealed that AML induction was less likely to achieve a CR as compared to ALL regimens, (WHO2008 odds ratio [OR] = 0.33, 95% confidence interval [95% CI] 0.18-0.58; EGIL, OR = 0.18, 95% CI 0.08-0.40). Multivariable analysis of the patient-level data supported poorer efficacy for AML induction (versus ALL: OR = 0.45 95% CI 0.27-0.77). Meta-analyses similarly found better OS for those beginning with ALL versus AML therapy (WHO2008 OR = 0.45, 95% CI 0.26-0.77; EGIL, OR = 0.43, 95% CI 0.24-0.78), but multivariable analysis of patient-level data showed only those starting with hybrid therapy fared worse (hazard ratio [HR] = 2.11, 95% CI 1.30-3.43). MPAL definition did not impact trends within each endpoint and were similarly predictive of outcome. Using either definition of MPAL, ALL-therapy is associated with higher initial remission rates for MPAL and is at least equivalent to more intensive AML therapy for long-term survival. Prospective trials are needed to establish a uniform approach to this heterogeneous disease.