The electrical transport property of layered MoSe2 has a strong response to high pressure by enhancing the inter-layer interaction. However, the narrowed bandgap under high pressure will cause the bipolar effect (i.e., the thermally excited minority carriers contribute to a Seebeck coefficient with the opposite sign to the majority carriers) at high temperatures to degrade the thermoelectric (TE) performance. Hence, suppressing the bipolar effect is important to optimize the TE performance of MoSe2 under high pressure and high temperature (HPHT). In this study, the degradation of TE performance caused by the bipolar effect under HPHT in MoSe2 is investigated. It is found that in MoSe2, the electrical conductivity was improved significantly by pressure; however, the bipolar effect led to a significantly degraded Seebeck coefficient at high temperatures. By injecting massive carriers beforehand, the bipolar effect was suppressed to make a dominant type of p-type charge carries, achieving an increased Seebeck coefficient with increasing temperature, resulting in an improved power factor from 29.3 μW m−1 K−2 in MoSe2 to 285.7 μW m−1 K−2 in Mo0.98Nb0.02Se2 at 5.5 GPa, 1110 K. Combined with the reduced thermal conductivity by point defect scattering on phonons, a maximum ZT value of 0.11 at 5.5 GPa, 1110 K. This work highlights the significance of suppressing the bipolar effect under HPHT for optimizing TE performance in such layered semiconductors.