In the present study, we aimed to fix the trigger parameters in the chemical synthesis of polypyrrole (PPy) using response surface methodology (RSM), based on central composite design (CCD) for high thermoelectric properties at room temperature up to 373 K. The RSM experimental design involved the investigation of three selected parameters [reaction time (t), oxidant (O) and dopant (D) concentrations] simultaneously. For this purpose, many reactions were performed in order to obtain thermoelectric efficiency responses, the so-called figure of merit (ZT). The bulk’s properties including electrical conductivity (σ), thermal conductivity (κ) and Seebeck coefficient (S) were respectively determined using the four-probes method, hot disc technique, and a homemade device. A second-order polynomial equation was used to model the relationship between the synthesis parameters and the figure of merit (ZT). A satisfactory R2 value of 0.83 was obtained from the regression analyses, suggesting good correlation between observed experimental values and predicted values by the second-order polynomial. The linear, quadratic and interaction terms of the considered parameters have a significant effect (P < 0.05) on the figure of merit (ZT). A reaction time of 20 min, an oxidant concentration of 0.1 mol and a dopant concentration of 0.005 mol were found to be the combinatorial optimal parameters for PPy synthesis resulting in improved thermoelectric properties, where the maximum value of the figure of merit (ZT) was around of 2.71 × 10−6. Moreover, several techniques like Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, x-ray photoelectron spectroscopy (XPS) and scanning electron microscopy were performed to characterize optimized PPy, and its characteristics were then correlated with their bulk properties.