Wood-based composites are finding increased applications over solid wood because of their important properties such as strength, aesthetic appearance, etc. to reuse the waste wood from other process and also because of the scarcity of solid wood. Medium density fiberboard (MDF) is a wood-based composite widely used in domestic, furniture manufacturing industries, construction, interior and exterior works. Machining process like drilling develops cutting force plays an important role in the quality of the final product. The cutting force developed can be controlled by the proper selection of input process parameters. The objective of this study is to analyze the influence of cutting conditions on the thrust force developed in drilling to predict the optimal cutting conditions of drilling parameters such as spindle speed, feed rate, and point angle. Taguchi design of experiments is used to perform the drilling tests. Response surface methodology (RSM) is used to develop the model to predict the influence of cutting parameters on thrust force and the adequacy of the developed model is checked with analysis of variance (ANOVA). It is revealed that the high spindle speed with low feed rate combination minimizes the thrust force in drilling of MDF panels.