High blood pressure (BP) may lead to further health complications if not monitored and controlled, especially for critically ill patients. Particularly, there are two types of blood pressure monitoring, invasive measurement, whereby a central line is inserted into the patient�s body, which is associated with infection risks. The second measurement is cuff-based that monitors BP by detecting the blood volume change at the skin surface using a pulse oximeter or wearable devices such as a smartwatch. This paper aims to estimate the blood pressure using machine learning from photoplethysmogram (PPG) signals, which is obtained from cuff-based monitoring. To avoid the issues associated with machine learning such as improperly choosing the classifiers and/or not selecting the best features, this paper utilized the tree-based pipeline optimization tool (TPOT) to automate the machine learning pipeline to select the best regression models for estimating both systolic BP (SBP) and diastolic BP (DBP) separately. As a pre-processing stage, notch filter, band-pass filter, and zero phase filtering were applied by TPOT to eliminate any potential noise inherent in the signal. Then, the automated feature selection was performed to select the best features to estimate the BP, including SBP and DBP features, which are extracted using random forest (RF) and k-nearest neighbors (KNN), respectively. To train and test the model, the PhysioNet global dataset was used, which contains 32.061 million samples for 1000 subjects. Finally, the proposed approach was evaluated and validated using the mean absolute error (MAE). The results obtained were 6.52 mmHg for SBS and 4.19 mmHg for DBP, which show the superiority of the proposed model over the related works. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.