The influence of the drilling parameters and the stacking sequence of flax/epoxy composite laminate on the cutting force and the damage induced were studied experimentally and numerically. Drilling tests were carried out based on full experimental design and the delamination at the entry and exit of the hole were quantified using an optical microscopy. Moreover, the damages at the wall of the hole were analyzed using scanning electron microscopy. Based on the experimental results, it was observed that the drilling forces and the machining quality are influenced on the one side by the spindle speed and feed and on the other side by the stacking sequence composite plate. In fact, the cutting forces recorded when drilling a composite plate with [90/0/90/0]2s is 30% higher to the one recorded when drilling a composite made with quasi-isotropic stacking sequence. A numerical model was developed in ABAQUS/Explicit using Hashin’s failure criteria in order to predict the cutting forces and the defects induced by the interaction of the drill and composite as a function of the machining parameters. The developed model has been validated at the macro-scale (thrust force) and the meso-scale (delamination at the entry and exit of the hole).