Nanofluidic thermoelectrics has attracted significant interest recently due to its potential for low-grade heat recovery. However, the impact of hydrodynamic slippage on power generation performance in nanofluidic channels has generally been ignored in previous studies, although slip velocity boundary conditions are relevant at the nanoscale. To fill this research gap, this study conducted two-dimensional (2D) numerical simulations based on non-isothermal Poisson, Nernst–Planck, Navier–Stokes, and energy equations to investigate the thermoelectric response, including Seebeck coefficient, thermoelectric current, power factor, and normalized maximum power density, within a nanochannel with slippage at the channel walls. The simulations considered three thermal-driven ion transport mechanisms: temperature-dependent ion electrophoretic mobility (TDIEM), Soret-type ion thermodiffusion, and thermoosmosis. The results showed that TDIEM and thermoosmosis primarily dominate the thermoelectric response of electrolyte confined in slip nanochannels in the presence of the overlapping electrical double layer. The study also found that the impact of access resistance on the thermoelectric response must be considered. The slip-enhancement of the Seebeck coefficient, i.e., the thermoelectric voltage at open-circuit condition, is not significant due to the increase in surface conductivity caused by slip-amplified electroosmosis, especially at low electrolyte concentrations. However, slip-amplified thermoosmosis greatly enhances the thermoelectric current at short-circuit condition, in the absence of the access resistance effect, leading to a significant improvement in the performance of ionic thermoelectricity in nanochannels with hydrodynamic slippage. At a moderate slip length ranging from 10 to 50 nm, it was found that the normalized maximum power density in a 2 nm nanochannel exceeded 10 mW K−2 m−2, even under a small temperature difference of 10 K, which is one order of magnitude higher than the typical thermionic capacitors and thermocells. Overall, this study provides valuable insights into developing efficient nanofluidic-based thermoelectric generators for low-grade heat energy harvesting by highlighting the importance of considering the effect of hydrodynamic slippage.