This article addresses an autonomous manipulation problem for an underwater vehicle-manipulator system (UVMS) operating in a free-floating way while subjecting to unknown continuous disturbance. More specifically, a composite control scheme composed of disturbance observer (DOB), predictor model network (PM-Net), and nonlinear model predictive control (NMPC), is devised to improve the control performance of UVMS (i.e., unicycle-like UVMS actuated only in the surge, heave, and yaw for vehicle body) in the case of disturbance, model mismatch, and input saturation. A RBF-DOB is formulated by combining a DOB and a Radial Basis Function (RBF) neural network to estimate disturbance at the current step. Then, the PM-Network, composed of a disturbance predictor network and state predictor network, is developed based on long short-term memory (LSTM) network that predicts UVMS state sequences considering model mismatch and disturbance. The NMPC is deployed as a feedback control law to endow the input saturation of the UVMS and produce optimal control action. Compared with conventional DOB control methods using feed-forward compensation of disturbance, the primary merit of the proposed approach is that the disturbance estimated by RBF-DOB is utilized in the PM-Net to predict future UVMS state sequences, which are exploited on the NMPC’s receding optimization. RGB0,0,0Finally, realistic simulation and relevant experiment are conducted to demonstrate the effectiveness of the proposed method. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Note to Practitioners</i> —The motivation behind this article is the autonomous manipulation of an underwater vehicle-manipulator system subjected to unknown disturbance. However, it is not always feasible or straightforward to obtain the external disturbance and unmodeled dynamics for designing robust controllers. On the one hand, how to manipulate the disturbance into the designed controller to generate optimal control action rather than by using feed-forward compensation. On the other hand, the control input saturation often occurs in the UVMS control, especially under the disturbance rejection conditions, where it should be considered in the controller design. Currently, the predominant methods for UVMS control lack a control scheme that provides a complete and credible control strategy that takes the aforementioned issues into consideration. Motivated by the above analysis, this study provides a composite control scheme to deal with the dynamic uncertainties, unknown disturbance, and input saturation. RGB0,0,0The results of realistic simulation and relevant experiments demonstrate the effectiveness of the proposed method. Hopefully, our control method can provide valuable theoretical and technical guidance to practicing marine engineers for controller design.