Time-domain numerical simulation is generally considered an accurate method to predict the mooring system performance, but it is also time and resource-consuming. This paper attempts to completely replace the time-domain numerical simulation with machine learning approaches, using a catenary anchor leg mooring (CALM) system design as an example. An adaptive sampling method is proposed to determine the dataset of various parameters in the CALM mooring system in order to train and validate the generated machine learning models. Reasonable prediction accuracy is achieved by the five assessed machine learning algorithms, namely random forest, extremely randomized trees, K-nearest neighbor, decision tree, and gradient boosting decision tree, among which random forest is found to perform the best if the sampling density is high enough.