Harvesting ambient mechanical energy is a key technology for realizing self-powered electronics. With advantages of stability and durability, a liquid–solid-based triboelectric nanogenerator (TENG) has recently drawn much attention. However, the impacts of liquid properties on the TENG performance and the related working principle are still unclear. We assembled herein a U-tube TENG based on the liquid–solid mode and applied 11 liquids to study the effects of liquid properties on the TENG output performance. The results confirmed that the key factors influencing the output are polarity, dielectric constant, and affinity to fluorinated ethylene propylene (FEP). Among the 11 liquids, the pure water-based U-tube TENG exhibited the best output with an open-circuit voltage (Voc) of 81.7 V and a short-circuit current (Isc) of 0.26 μA for the shaking mode (0.5 Hz), which can further increase to 93.0 V and 0.48 μA, respectively, for the horizontal shifting mode (1.25 Hz). The U-tube TENG can be utilized as a self-powered concentration sensor (component concentration or metalion concentration) for an aqueous solution with an accuracy higher than 92%. Finally, an upgraded sandwich-like water-FEP U-tube TENG was applied to harvest water-wave energy, showing a high output with Voc of 350 V, Isc of 1.75 μA, and power density of 2.04 W/m3. We successfully lighted up 60 LEDs and powered a temperature–humidity meter. Given its high output performance, the water-FEP U-tube TENG is a very promising approach for harvesting water-wave energy for self-powered electronics.