Additive manufacturing provides achievability for the fabrication of bimetallic and multi-material structures; however, the material compatibility and bondability directly affect the parts’ formability and final quality. It is essential to understand the underlying printability of different material combinations based on an adapted process. Here, the printability disparities of two common and attractive material combinations (nickel- and iron-based alloys) are evaluated at the macro and micro levels via laser directed energy deposition (DED). The deposition processes were captured using in situ high-speed imaging, and the dissimilarities in melt pool features and track morphology were quantitatively investigated within specific process windows. Moreover, the microstructure diversity of the tracks and blocks processed with varied material pairs was comparatively elaborated and, complemented with the informative multi-physics modeling, the presented non-uniformity in mechanical properties (microhardness) among the heterogeneous material pairs was rationalized. The differences in melt flow induced by the unlike thermophysical properties of the material pairs and the resulting element intermixing and localized re-alloying during solidification dominate the presented dissimilarity in printability among the material combinations. This work provides an in-depth understanding of the phenomenological differences in the deposition of dissimilar materials and aims to guide more reliable DED forming of bimetallic parts.