To track the rapidly changing temperature profiles of thermal cycling of polymerase chain reaction (PCR) accurately, an innovative feedforward variable structural proportional-integral-derivative (FVSPID) controller was developed. Based on the step response test data of the heat block, a reduced first order model was established at different operating points. Based on the reduced model, the FVSPID controller combined a feedforward path with the variable structural proportional-integral-derivative (PID) control. The modified feedforward action provided directly the optimal predictive power for the desired setpoint to speed up the dynamic response. To cooperate with the feedforward action, a variable structural PID was applied, where the P mode was used in the case of the largest errors to speed up response, whereas the PD mode was used in the case of larger errors to suppress overshoot, and finally the PID mode was applied for small error conditions to eliminate the steady state offset. Experimental results illustrated that compared to the conventional PID controller, the FVSPID controller can not only reduce the time taken to complete a standard PCR protocol, but also improve the accuracy of gene amplification.