Wnt5a is a non‐canonical Wnt protein that is expressed at elevated levels in inflammatory conditions. Its role in inflammation remains unclear, although it is known that Wnt5a is expressed at a higher level in monocyte‐derived myeloid dendritic cells (Mo‐mDCs) than in monocytes and macrophages. The function of Wnt5a in dendritic cells (DCs) remains relatively unexplored. Here, we found that under Mo‐mDC culture conditions, Wnt5a inhibited the generation of CD14^+/low Mo‐mDCs while promoting the generation of CD14^+/++ CD16⁺ monocytes. We could further show that stimulation of monocytes with rWnt5a induced a rapid IL‐6 production and that the rWnt5a treated Mo‐mDC differentiation was restored upon blocking of IL‐6. Also, conditioned media from Wnt5a stimulated human breast cancer cells producing IL‐6, specifically inhibited Mo‐mDC differentiation. These observations are strengthened by our finding that patients with sepsis, a disease involving elevated Wnt5a and IL‐6 levels, also showed a significant increase in the CD14⁺ CD16⁺⁺/CD14^+/++ CD16⁺ monocyte populations, which was accompanied by a significant decrease in circulating mDCs. We finally show that under typical Mo‐mDC culture conditions, monocytes isolated from patients with sepsis as compared to healthy controls, preferentially differentiated into CD14^+/++ HLA‐DR⁺⁺ cells. We suggest that Wnt5a is a possible candidate mediator for the CD14^+/++ CD16⁺ monocyte accumulation seen in patients with infectious disease and cancer.