In trying to discover the potential genes or strategies used to regulate the morphology of Rhizopus oryzae, cells in different morphological states were subjected to transcriptomic and metabolomic analyses. The results showed that the tricarboxylic acid cycle was down-regulated in the pellet sample, whereas the metabolism of pyruvic acid, unsaturated fatty acids, and amino acids, as well as the synthesis of sugar alcohols, were up-regulated. Moreover, an increase of oxidative stress markers was detected during pellet formation. In response to this stress, R. oryzae up-regulated the aforementioned pathways and induced a number of antioxidant enzymes. In addition, R. oryzae adapted its cell wall composition to reduce the surface area exposed to the environment. Following these findings, hemicellulose hydrolysate was added into the culture medium, which led to the formation of uniform pellets over a broad pH range. This study might provide clues to deduce the unequivocal general relationships between process variables and fungal morphology.