You are calling the wrong methods. You hardly ever need to use the SetDefine method.
using (MagickImage image = new MagickImage(origPATH)) { image.Format = MagickFormat.Png; //image.SetDefine(MagickFormat.Png, "colors", "128"); QuantizeSettings settings = new QuantizeSettings(); settings.Colors = 128; image.Quantize(settings); //image.SetDefine(MagickFormat.Png, "depth", "8"); image.Depth = 8; //image.SetDefine(MagickFormat.Png, "resample", "72"); image.Resample(72, 72); image.Write(targetPATH); }