Background: Euphorbia is one of the plants most used by herbalists and therapists in Morocco. Objectives: The aerial part of two plant samples (Euphorbia resinifera and Euphorbia officinarum) collected in Morocco was examined for the solvent effect, extraction time, and plant concentration in order to determine the best extraction conditions. Materials and Methods: To achieve this goal, a response surface methodology (RSM) using a full three-level factorial design was used to optimize the conditions for the extraction of antioxidants and α-glucosidase inhibitors. Temperature, time, and plant-to-solvent ratio (PSR) and their linear and quadratic interactions on TPC (total phenol concentration), TFC (total flavonoid concentration), DPPH (2,2-diphenyl-1-picrylhydrazyl) trapping activity, and α-glucosidase inhibiting activities were studied. Results: According to desirability functions, the optimum operating conditions to achieve a higher extraction yield of phenols and higher antioxidant and anti-diabetic activity were found by using extraction during 60 min at 30°C using a PSR of 20 mg/mL, whereas a longer extraction time (270 min) was needed for E. resinifera and a higher extraction temperature (50°C), with a lower PSR (10 mg/mL) for E. officinarum. Conclusion: In order to find the best conditions to extract secondary metabolites with biological activity and application in phytotherapy, the appropriate solvent generally used by populations, water in this case, should be used, but the best extraction conditions have to be found in order to enhance the pharmacological actions.