The original cellular structure and the presence of starch are known to reduce quinoa protein digestibility. Here, we aimed at optimizing an integrated single-step process exploiting the synergisms of amylolysis (<0.42%, starch basis) and extrusion (at different temperature profiles) to enhance protein digestibility in saponin-free quinoa flour while minimizing polyphenol losses. Protein digestion rate (velocity of substrate depletion) and extension (percentage of digested substrate at the end of the reaction) were significantly enhanced with every extrusion treatment, reaching up to four-fold faster protein digestion rate and up to 47% reduction of residual non-digested protein at 100 °C (last barrel temperature) and 0.36 g/100 g α-amylase concentration compared to native flour. Generally, reactive extrusion lowered the content of extractable (free) polyphenols and non-extractable proanthocyanins, but this effect was minimized at lower extrusion temperatures and higher α-amylase concentration. Contrarily, the more thermoresistant hydrolysable bound polyphenols increased in all cases, especially at harsh extrusion conditions.