Polymer brushes, an optimal method for surface modification, have garnered significant interest due to their potential in surface wettability and functions regulation. This review summarizes the recent advancements in functional polymer brush surfaces based on surface wettability regulation. First, the fundamental structure and fabrication methods of polymer brushes, emphasizing the two primary strategies, “grafting-to” and “grafting-from”, were introduced, and special attention was accorded to the method of subsurface-initiated atom transfer radical polymerization (SSI-ATRP) for the construction of mechanically robust polymer brushes. Subsequently, we delved into the attributes of the stimuli-responsive polymer brush surface, which can effectuate reversible surface wettability transitions in response to external stimuli. Then, this review also offered an in-depth exploration of the potential applications of polymer brushes based on their surface wettability, including lubrication, drag reduction, antifouling, antifogging, anti-icing, oil–water separation, actuation, and emulsion stability. Lastly, the challenges of polymer brush surfaces encountered in practical applications, including mechanical strength, biocompatibility, recyclability, and preparation efficiency, were addressed, and significant achievements in current research were summarized and insights into future directions were offered. This review intends to provide researchers with a comprehensive understanding of the potential applications of polymer brushes based on surface wettability regulation, and with the development of the polymer brush preparation technology, it will be anticipated that they will assume increasingly pivotal roles in various fields.