Introduction: Annona muricata L. (soursop) is used in ethnomedicine for the treatment of various diseases. Leaves of this species have been found to contain flavonoids, which are compounds with antidiabetic, antioxidant and anti-inflammatory properties. Objective: optimization of operational parameters on the solid–liquid extraction of flavonoids from A. muricata leaves. Methods: Evaluation of the operational variables was based on Composite Center Design (CCD) of Response surface methodology (RSM), selecting the intervals between 50 and 70 ml/g for the plant material / solvent volume ratio, 40% to 80% for ethanol concentration and 2 to 3 h for extraction time. Flavonoids and quercetin were found in the extracts obtained. Total flavonoids were quantified using a colorimetric method at 430 nm, expressed as quercetin. Experiments were conducted in triplicate to determine the best experimental condition. Comparison with the design value predicted showed a good correlation between the two. Results: the optimal condition for extraction of total flavonoids was reached at an ethanol concentration of 96%, a 70 ml/g ratio and a time of 1.6 h. The variables found to be significant were the quadratic effects of the plant material / solvent volume ratio and ethanol concentration. Conclusions: a selection was made of the best conditions to obtain an extract from soursop leaves containing flavonoids, in which an extraction output of 87% was achieved in the extraction process.