During infection, TLR agonists are released and trigger mature as well as differentiating innate immune cells. Early encounter with TLR agonists (R848; LPS) blocks conventional differentiation of CD14⁺ monocytes into immature dendritic cells (iDCs) resulting in a deviated phenotype. We and others characterized these APCs (TLR‐APC) by a retained expression of CD14 and a lack of CD1a. Here, we show in addition, expression of programmed death ligand‐1 (PD‐L1). TLR‐APCs failed to induce T‐cell proliferation and furthermore were able to induce CD25⁺Foxp3⁺ T regulatory cells (Tregs). Since PD‐L1 is described as a key negative regulator and inducer of tolerance, we further analyzed its regulation. PD‐L1 expression was regulated in a MAPK/cytokine/STAT‐3‐dependent manner: high levels of IL‐6 and IL‐10 that signal via STAT‐3 were produced by TLR‐APCs. Blocking of STAT‐3 activation prevented PD‐L1 expression. Moreover, chromatin immunoprecipitation revealed direct binding of STAT‐3 to the PD‐L1 promoter. Those findings indicate a pivotal role of STAT‐3 in regulating PD‐L1 expression. MAPKs were indirectly engaged, as blocking of p38 and p44/42 MAPKs decreased IL‐6 and IL‐10 thus reducing STAT‐3 activation and subsequent PD‐L1 expression. Hence, during DC differentiation TLR agonists induce a STAT‐3‐mediated expression of PD‐L1 and favor the development of tolerogenic APCs.