Liquid-infused surfaces have recently gained prominence in engineering applications owing to their versatile characteristics such as self-cleaning, anti-fogging, drag reduction, and enhanced heat transfer. In this article, a numerical analysis of pressure-driven flow past a periodic array of rectangular transverse grooves infused with non-Newtonian immiscible lubricants is performed. The volume of fluid method is employed to capture the interface between primary and secondary fluids, and the power-law model is deployed to mimic the non-Newtonian lubricant. The drag reduction capability of the microchannel is examined for various parameters such as Reynolds number, liquid fraction, viscosity ratio, viscosity index, and contact angle. It is observed that the introduction of a non-Newtonian fluid (shear-thickening or shear-thinning) drastically modifies the interface velocity and hydrodynamic resistance. In particular, a shear-thinning lubricant enhances the slip length as the viscosity index (n) is reduced owing to the reduced viscosity at the interface. Note that, for a lubricant having n = 0.7, the percentage improvement in the slip length is 382% in comparison with a Newtonian counterpart having the same viscosity ratio, N = 0.1. Importantly, the introduction of a shear-thinning lubricant with a viscosity ratio N = 5, a liquid fraction of 0.8, and a behavior index n = 0.7 yielded a pressure drag reduction of 63.6% with respect to a classical no-slip channel and of 23% with reference to a microchannel with the Newtonian lubricant. Moreover, at high Reynolds numbers, Re→50, the drag mitigation is slightly lowered due to the primary vortex shift in the cavity. Furthermore, the effect of the interface contact angle (θc) is investigated, as θc drops from 90° (flat) to 45° (convex); the meniscus curvature is enhanced, and the effective slip length is reduced. These observations suggest that a shear-thinning lubricant-infused microchannel is a promising candidate for drag reduction in lab-on-chip applications.