The almond cake is a protein- and oil-rich by-product of the mechanical expression of almond oil that has the potential to be used as a source of valuable proteins and lipids for food applications. The objectives of this study were to evaluate the individual and combined effects of solids-to-liquid ratio (SLR), reaction time, and enzyme use on oil and protein extraction yields from almond cake. A central composite rotatable design was employed to maximize the overall extractability and distribution of extracted components among the fractions generated by the aqueous (AEP) and enzyme-assisted aqueous extraction process (EAEP). Simultaneous extraction of oil and protein by the AEP was favored by the use of low SLR (1:12.82) and longer reaction times (2 h), where extraction yields of 48.2% and 70% were achieved, respectively. Increased use of enzyme (0.85%) in the EAEP resulted in higher oil (50%) and protein (75%) extraction yields in a shorter reaction time (1 h), compared with the AEP at the same reaction time (41.6% oil and 70% protein extraction). Overall, extraction conditions that favored oil and protein extraction also favored oil yield in the cream and protein yield in the skim. However, increased oil yield in the skim was observed at conditions where higher oil extraction was achieved. In addition to improving oil and protein extractability, the use of enzyme during the extraction resulted in the production of skim fractions with smaller and more soluble peptides at low pH (5.0), highlighting possible uses of the EAEP skim in food applications involving acidic pH. The implications of the use of enzyme during the extraction regarding the de-emulsification of the EAEP cream warrant further investigation.