The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uses endoplasmic reticulum membranes and associated human proteins for its replication and to evade detection. One human protein recruited by several viral proteins is selenoprotein S, which takes part in the endoplasmic reticulum protein degradation pathway, NFkB signaling, and cytokines secretion. A key interaction was reported with SARS-CoV-2 non-structural protein (nsp7), which is essential for virus replication. However, it was unclear whether selenoprotein S and nsp7 interact directly and whether the interaction is possible when nsp7 forms a complex with the other components of the virus's replication machinery. We used biochemical assays to show that selenoprotein S binds nsp7, including when nsp7 is in complex with the coronavirus's RNA-dependent RNA polymerase. This places selenoprotein S at the heart of the coronavirus's replication complex and marks it as the first human protein shown to directly interact with the viral replication complex. Cross-linking experiments were employed to map the interactions of selenoprotein S and nsp7 in the replication complex. We show that the hydrophobic segment of selenoprotein S is essential for binding nsp7. This arrangement leaves an extended helix and the intrinsically disordered region of selenoprotein S exposed and free to recruit additional proteins to the complex.