The influence of casein-to-whey protein ratio (C:WP; 40:60, 60:40, 80:20) on the digestibility of infant formula powder was studied using an in vitro digestion model. With increasing C:WP, more extensive coagulation in samples was observed through particle size and confocal microscopy analyses. Coagulum particles consisted of a protein matrix in which emulsion droplets were embedded. The more extensive coagulation also led to significant (p < 0.05) reductions in protein and fat digestion during gastric and intestinal stages of digestion. These reductions can be attributed to reduced accessibility of digestive enzymes to their respective substrates. Gastric coagulation of the caseins was less extensive and digestion of protein and lipid was highest at C:WP of 40:60, which closely resembled human milk. The strong effects of C:WP on the digestion of infant formula further highlight the importance of the gastric coagulation process to ensure efficient digestion of protein and fat.