Biomaterials are known to modulate immune cell functions, which subsequently determine the host inflammatory and immune responses. Poly(lactic‐co‐glycolic acid) or PLGA, a biodegradable and biocompatible biomaterial, induces a pro‐inflammatory, mature phenotype in antigen presentation cells, namely dendritic cells (DCs) in vitro. In vivo, PLGA can boost the humoral immune response to a co‐delivered model antigen, a phenomenon known as the PLGA‐adjuvant effect. This study elucidates the link between PLGA's effect on the DC phenotype in vitro and its adjuvant effect in vivo using the CD11c‐DTR mouse model. These mice undergo conditional ablation of DCs upon treatment with diphtheria toxin. To measure immune activation, the mice were first given ovalbumin (OVA)‐reactive T cells from OT‐II/OT‐I mice. Later, the same mice received subcutaneous OVA‐loaded PLGA scaffold implants. In response to the scaffold implants, OVA‐reactive OT‐II CD4+ T cells showed decreased proliferation in the absence of CD11c+ DCs, indicating an attenuation of the PLGA‐adjuvant effect. Furthermore, PLGA may also influence the antigen cross‐presentation function of DCs, as evident with the lowered OVA‐reactive OT‐I CD8+ T‐cell response. Understanding the immunomodulatory ability of biomaterials in the context of DCs will aid in designing improved DC‐based immunotherapies against infectious diseases and cancer.