The value of serial lung ultrasound (LUS) in patients with COVID-19 is not well defined. In this multicenter prospective observational study, we aimed to assess the prognostic accuracy of serial LUS in patients admitted to hospital due to COVID-19. The serial LUS protocol included two examinations (0–48 h and 72–96 h after admission) using a 10-zones sequence, and a 0 to 5 severity score. Primary combined endpoint was death or the need for invasive mechanical ventilation. Calibration (Hosmer–Lemeshow test and calibration curves), and discrimination power (area under the ROC curve) of both ultrasound exams (SCORE1 and 2), and their difference (DIFFERENTIAL-SCORE) were performed. A total of 469 patients (54.2% women, median age 60 years) were included. The primary endpoint occurred in 51 patients (10.9%). Probability risk tertiles of SCORE1 and SCORE2 (0–11 points, 12–24 points, and ≥25 points) obtained a high calibration. SCORE-2 showed a higher discrimination power than SCORE-1 (AUC 0.72 (0.58–0.85) vs. 0.61 (0.52–0.7)). The DIFFERENTIAL-SCORE showed a higher discrimination power than SCORE-1 and SCORE-2 (AUC 0.78 (0.66–0.9)). An algorithm for clinical decision-making is proposed. Serial lung ultrasound performing two examinations during the first days of hospitalization is an accurate strategy for predicting clinical deterioration of patients with COVID-19.