Energy and mass transfer process are involved in many industries, such as energy, transportation, aeronautics and astronautics, electronic, manufacturing, among which, the heat exchanger plays a very key role. With the development of science and technology and the increasing requirements for energy conservation and emission reduction, the efficiency of heat exchange system has to be promoted to meet the demand of higher heat intensity and thermal load. The high-efficient and energy-saving compact heat exchanger such as microchannel heat sink has gained more attractions in academic researches and engineering applications. Microchannel with pin-fin is widely used in engineering applications due to its high efficiency in heat and mass transfer, but the high temperature region formed in the rear of the cylinder and the non-uniformity temperature field increase the temperature gradient and generate extra thermal spreading resistance, which would, to a large extend, influence the regulation of the system and the economy and reliability of the equipments. Therefore, the endwall fillet structure is proposed in this work, based on researches about the performance of CDA (controlled diffusion airfoil) blade with fillet, to improve the temperature uniformity and heat transfer performance of microchannel with pin-fin. The periodical laminar flow and heat transfer performances are comparatively studied. The results show that the flow resistance coefficient f of the microchannel with filleted pin-fin does not increase significantly compared to traditional pin-fined microchannel, which means the introducing of the fillet will enhance the heat transfer while f of the microchannel is almost a constant. The maximum increase of f is only 2.03%. Moreover, two separate symmetrical secondary flows develop in microchannel with smooth cylinder, with one on the top of the other. After adding the proposed structures, at low Reynolds number, the lower span-wise secondary flow is enhanced as the radius increases and these two span-wise secondary flows gradually merge into one which develops along the normal direction. At high Reynolds number, the mainstream low-temperature core region is obvious asymmetry: it moves downwards gradually as Reynolds number increases. Besides, at low Reynolds number (0–120), the fillet improves the heat and mass transfer between the main stream core and areas near the wall, enhances the thermal uniformity of the pin-fin and heated walls, improves the heat transfer performance of the rear of the cylinder and eliminates the high temperature area in the pin-fin. And local high-temperature region on the top half of the microchannel decreases, which contributes to the extension of low-temperature region and the decrease of average temperature. As the radius of the fillet increases, the effects mentioned above are gradually enhanced. The heat transfer coefficient of the channel reaches a maximum augmentation of 16.93%, and the flow resistance coefficient of the microchannel with filleted pin-fin does not increase significantly. Comparing with the synthetical thermal performance coefficient of pin-fined microchannel heat sink, that of the proposed filleted pin-fin microchannel increases 16.22% at most. As the Reynolds number increases, the influence of the fillet structure decreases. The study motivation of combining separation flow researches of rotatory machines with heat transfer enhancement, as well as the resulting design are a beneficial attempt for scientific research and engineering application.