Nanomaterials used can significantly improve the analytical performance of optical sensors to environmental pollutants. Two-dimensional (2D) molybdenum sulfide (MoS2) exhibits some unique physicochemical properties such as strong light-matter interaction, bandgap tunability, and high carrier mobility, which are beneficial for constructing flexible optoelectronic devices. In this Review, the principle and classification of 2D MoS2-based photodetectors (PDs) are introduced, followed by a discussion about the physicochemical properties of 2D MoS2, as well as structure-property relationships of 2D MoS2-based photoactive materials for PDs to understand the modulation strategies for enhancing the photodetection performance. Furthermore, we discuss significant advances in the surface modification and functionalization of 2D MoS2 for developing high-performance PDs, particularly focusing on synthesis pathways, modification strategies, and underlying physiochemical mechanisms for enhanced photodetection capabilities. Finally, conclusions and research perspectives on resolving significant bottlenecks or remaining challenges are offered based on recent developments in 2D MoS2-based PDs.