Macrophage polarization has been well documented. Macrophages can aquire two phenotypes, the pro-inflammatory M1 phenotype, and the anti-inflammatory and wound healing M2 phenotype. The M1 macrophage phenotype has been linked to metabolic disease and is also associated with cancer-related inflammation. Of note, macrophage polarization can be influenced by the extracellular environment. In the current study, we examined the effects of Pyropia yezoensis glycoprotein (PYGP) on M1 to M2 macrophage polarization in lipopolysaccharide (LPS)-stimulated macrophages. RAW 264.7 macrophages stimulated with LPS exhibited an upregulated expression of pro-inflammatory mediators, namely of the M1 markers, nitric oxide (NO), reactive oxygen species (ROS), interleukin (IL)-6, IL-1β, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and nitric oxide synthase‑2 (NOS-2). Treatment with PYGP inhibited the production of M1 markers and increased arginase 1 (ARG1), chitinase-like 3 (Chil3; also known as Ym1), resistin like beta (RETNLB; also known as FIZZ1), IL-10, CD163, CD206, peroxisome proliferator-activated receptor γ (PPARγ) and Krüppel-like factor 4 (KLF4) M2 marker gene expression. The signal transducer and activator of transcription (STAT)3 and STAT6 transcription factors were phosphorylated following treatment with PYGP. However, the silencing of STAT3 and STAT6 using siRNA in the macrophages decreased ARG1, Ym1 and FIZZ1 M2 marker gene expression in spite of treatment of PYGP. These findings suggest that PYGP exerts anti-inflammatory effects by regulating the M1 to M2 phenotypic switch through STAT3 and STAT6. Thus, PYGP may have potential for use as a natural remedy for inflammatory diseases.