Objectives: Venetoclax combinations are a new standard for patients with acute myeloid leukemia (AML). We aimed to evaluate the safety and efficacy of these combinations in a period of accelerated approval in Latin-America. Methods: This observational study evaluated adults with acute myeloid leukemia who received venetoclax-based therapy in 11 public or private centers in Mexico and Peru for both newly diagnosed or relapsed and refractory AML. Results: Fifty patients were included; 28 with newly diagnosed (ND) AML and 22 with relapsed/refractory (RR) disease. ND patients were older (64 vs. 40 years; p < 0.001) with a lower functional capacity (ECOG ≥2 64.3% vs 9%; p < 0.001). Venetoclax was frequently combined with azacytidine (60%) and prophylactic azoles (82%) with a median maximum dose of 200 mg (range, 100–600 mg). Hematologic toxicities were common. Complete response rates including patients with incomplete hematopoietic recovery were 78.6% in ND and 45.5% in RR patients, with a median overall survival of 9.6 (95% CI 3.7–15.5) and 8 months (95% CI 4.8–11.2). Discussion: Our study showed a preferred use of venetoclax plus azacytidine over cyatrabine. Patients in the first-line setting were similar to those in the landmark studies, while most patients with relapsed disease had received prior intensive therapies. Responses were favorable, with a median survival in agreement to other reports, albeit shorter than that observed in the randomized phase-3 trials. Conclusion: Venetoclax-based therapy in AML was effective despite dose reductions and prophylactic antifungals in two middle-income countries outside of a clinical trial setting.