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In this study, the hydraulic and thermal performances of dissimilar particles of alumina–silica/water hybrid nanofluid are experimentally investigated in a minichannel heat sink. Stable alumina–silica/water hybrid nanofluid is used as a coolant having a volume concentration of 0.01%. A total of 12 rectangular minichannels with 1 mm depth, 1 mm width, and a hydraulic diameter of 22 mm are used. The effect of Reynolds number on the Nusselt number, heat transfer coefficient, thermal resistance, pressure drop, pumping power, and friction factor are analyzed for various heating powers. Results indicate that the alumina/silica hybrid nanofluid can enhance heat transfer and pressure drop in a straight minichannel heat sink as compared with the base fluid (water). For heating power at 55 W, the use of hybrid nanofluid enhances heat transfer rate, pressure drop, and thermal performance up to 13.79%, 4.35%, and 31.16%, respectively. Moreover, it can be concluded that heating power had a significant effect on pressure drop and heat transfer for hybrid nanofluids. Finally, the performance evaluation criteria (PEC) for all nanofluids in a straight minichannel heat sink is always greater than one.