KDEL receptor homologs 1-3 (KDELR1-3) are seven-pass membrane proteins involved in secretory homeostasis in Golgi and endoplasmic reticulum (ER). Binding of a semi-conserved Lys-Asp-Glu-Leu (“K-D-E-L”) chaperone sequence to KDELRs in the Golgi lumen initiates extensive membrane trafficking resulting in chaperone retrieval to ER and cargo release from Golgi. Aberrations in KDELR secretory signaling manifest in a wide range of diseases such as invasive cancers, dilated cardiomyopathy, neurodegeneration, and susceptibility to viral infections. At present, the role of anionic lipids in modulation of KDELR structure-function is not well understood. This is a major knowledge-gap as anionic lipids are crucial modulators of membrane dynamics, such as in the stabilization of integral membrane protein conformations and in recruitment of cytosolic signaling and trafficking proteins. In this investigation, we report interactions of KDELRs with a large panel of physiological anionic lipids that vary in headgroup composition and charge. Although KDELR homologs demonstrate differences in specificity for anionic lipids, KDELR1 and KDELR2, which share 94% sequence similarity, demonstrate broad interactions with anionic lipids enriched in the membrane cytosolic leaflet. KDELR3, on the other hand, demonstrates selectivity in interactions with anionic lipids. An in-silico Site-Identification by Ligand Competitive Saturation (SILCS) docking analysis of KDELR2 identifies multiple binding sites for anionic lipids. The residues in these sites are semi-conserved in KDELR homologs, thus providing residue-level insights into KDELR-lipid interactions. Molecular dynamics simulations demonstrate conformational modulation of KDELR2 by anionic lipids in a bilayer. The results generated in this investigation advance the biophysical and computational understanding of how membranes modulate KDELR conformations, thus controlling initiation of secretory trafficking.