A Class-F mode-based power amplifier (PA) with optimized efficiency in triple-band was designed using a simple and systematic approach. By considering the second and third harmonic terminations of the PA, the relationship between the output impedance design space and the drain efficiency (DE) is extracted by large-signal model simulation. Then, a low-pass matching topology is utilized for the triple-band efficiency optimization. The method is justified by both simulation and measurement of a triple-band PA to integrate three functions into one hardware, i.e., 1518–1525 MHz for mobile communication, 2.1 GHz for telemetry and control, and 2.492 GHz for navigation signal transport. The proposed PA achieves a measured result of high DE (63% at 1.52 GHz, 71% at 2.1 GHz, 59% at 2.492 GHz) in the three bands with an output power of at least 40 dBm.