Three isocaloric (3.5 kcal/g) ingredient blends containing 20, 30, and 40% (wb) distillers dried grains with solubles (DDGS) along with soy flour, corn flour, fish meal, and mineral and vitamin mix, with net protein adjusted to 28% (wb) for all blends, were extruded in a single-screw laboratory-scale extruder at screw speeds of 100, 130, and 160 rpm, and 15, 20, and 25% (wb) moisture content. Increasing DDGS content from 20 to 40% resulted in a 37.1, 3.1, and 8.4% decrease in extrudate durability, specific gravity, and porosity, respectively, but a 7.5% increase in bulk density. Increasing screw speed from 100 to 160 rpm resulted in a 20.3 and 8.8% increase in durability and porosity, respectively, but a 12.9% decrease in bulk density. On the other hand, increasing the moisture content from 15 to 25% (wb) resulted in a 28.2% increase in durability, but an 8.3 and 8.5% decrease in specific gravity and porosity, respectively. Furthermore, increasing the screw speed and moisture content of the blends, respectively, resulted in an increase of 29.9 and 16.6% in extruder throughput. The extrudates containing 40% DDGS had 8.7% lower brightness, as well as 20.9 and 16.9% higher redness and yellowness, compared with the extrudates containing only 20% DDGS. Increasing the DDGS content from 20 to 40% resulted in a 52.9 and 51.4% increase in fiber and fat content, respectively, and a 7.2% decrease in nitrogen free extract. As demonstrated in this study, ingredient moisture content and screw speed are critical considerations when producing extrudates with ingredient blends containing DDGS, as they are with any other ingredients.