Microwave power transmission (MPT) is one of the most promising techniques to achieve long-distance wireless power transmission. Working in radio frequency (RF), the transmission line (TL) topology of class E power amplifier (PA) is an essential candidate for the MPT system, acting as the role of DC-RF conversion. PA’s performance significantly affects the efficiency of the whole system. However, there are few specific accurate design methods of TL class E PA. This paper presents a novel method to design TL class E PA in a mathematical way. The proposed method can strictly convert lumped element topology of class E PA to TL topology, regardless of different types of matching network. To minimize impedance discontinuities in the TL topology, an optimal strategy is also presented. The proposed strategy can help reduce return loss and increase power added efficiency (PAE). A 2.5GHz/10W high efficiency TL class E PA is constructed to verify the proposed method and the optimal strategy. As all simulation and experimental results indicate, the proposed method can accomplish a precise design of high efficiency TL class E PA.