Engineered gold nanoparticles (GNPs) have become a useful tool in various therapeutic and diagnostic applications. Uncertainty remains regarding the possible impact of GNPs on the immune system. In this regard, we investigated the interactions of polymer-coated GNPs with B cells and their functions in mice. Surprisingly, we observed that polymer-coated GNPs mainly interact with the recently identified subpopulation of B lymphocytes named age-associated B cells (ABCs). Importantly, we also showed that GNPs did not affect cell viability or the percentages of other B cell populations in different organs. Furthermore, GNPs did not activate B cell innate-like immune responses in any of the tested conditions, nor did they impair adaptive B cell responses in immunized mice. Together, these data provide an important contribution to the otherwise limited knowledge about GNP interference with B cell immune function, and demonstrate that GNPs represent a safe tool to target ABCs in vivo for potential clinical applications.