Mechanically pumped two-phase loop (MPTL), as an emerging two-phase heat dissipation transformational technique, has made booming progress in some critical but tough cases such as space stations and high-performance chips. However, accurate temperature regulation of MPTL is intractable due to periodic heat load disturbance, measurement noise, and micro-channel boiling nonlinearity. To address these issues, an extended state observer-based model predictive control (ESOMPC) strategy is developed in this paper. To describe the process model, this paper builds an MPTL platform equipped with a micro-channel evaporator, based on which a series of sinusoidal heat load variation is carried out to show the effects on the wall temperature. Open-loop step experiments are then conducted in terms of flow rate of the working fluid so that the process model can be identified and the nonlinearity can be analyzed. Then, the ESOMPC is developed by incorporating the disturbance information in the optimization framework of the MPC. The ESO part is utilized to estimate the unknown disturbances and compensate the nonlinearity of MPTL, and thus enhance the disturbance mitigation property of the MPC algorithm. Finally, the closed-loop experiments verifies the efficacy of the proposed solution, showing smaller temperature fluctuation and shorter settling time than the conventional controller. The results indicate the great potential of the proposed ESOMPC in enhancing the temperature control accuracy of MPTL in terms of thermal management performance.