Respiratory mechanical parameters of ventilated patients are usually referred in the respiratory diagnosis and treatment. However, the effectiveness of the modern estimation methods is limited. To estimate the overall breathing resistance, overall respiratory compliance, and residual volume simultaneously, a new mathematical model of mechanical ventilation system was proposed. Furthermore, to improve the estimation accuracy, the noise model of mechanical ventilation system was taken into consideration. Based on the mathematical model, a respiratory mechanical parameters estimation method based on extended least squares (ELS) algorithm was derived. Finally, to test the respiratory mechanical parameters estimation method, it was studied experimentally and numerically, and it was approved that the proposed method is effective to estimate the three respiratory mechanical parameters simultaneously and precisely. The estimated values of the parameters can be adopted in the clinical practice. The study provides a new method to estimate respiratory mechanical parameters.