Prognostic significance of elevated serum lactate in patients on venoarterial extracorporeal membrane oxygenation (ECMO) is widely known. Our objective was to study the utility of lactate measured at different points of time and lactate clearance in predicting the two study endpoints: successful ECMO weaning and hospital survival. Among 238 consecutive patients treated with ECMO, lactic acid was collected before initiating ECMO and then on days 1, 3, 5, and 10 while on ECMO. Out of our cohort, 129 (54.2%) were successfully weaned and 98 (41.2%) were discharged alive. Patients successfully weaned from ECMO had a significantly lower lactic acid level pre-ECMO (p = 0.001), at day 1 (p < 0.001), day 3 (p < 0.001), and day 5 (p = 0.001), compared with unsuccessfully weaned patients. Also, patients who survived hospitalization had significantly lower lactic acid pre-ECMO (p = 0.007), at day 1 (p < 0.001), day 3 (p = 0.001), and day 5 (p = 0.001), compared with those who died in-hospital. With regard to hospital survival, day 3 lactic acid was superior to pre-ECMO lactic acid (p = 0.0385), lactic acid on day 1, lactic acid reduction from pre-ECMO to day 1 (p = 0.0177) and from pre-ECMO to day 3 (p = 0.0361), and a day 3 lactic acid ≤ 1.7 meq/L was the optimal value that predicted hospital survival. On multivariable analysis, day 3 lactic acid independently predicted hospital survival after covariate adjustment (odds ratio [OR], 0.505; 95% confidence interval [CI], 0.290–0.880; p = 0.016). In conclusion, the absolute level of lactic acid while on ECMO support is more important for prognosis than a pre-ECMO level or the magnitude of decline from pre-ECMO to on-ECMO.