In this study, a special resolution V design and Response surface methodology (RSM) were used to characterize the ultrasonic-assisted drilling (UAD) process of Aluminum 6061. This characterization was done through developing mathematical models to study the effect of ultrasonic and drilling parameters including spindle speed, feed rate and amplitude on thrust force, temperature, chip morphology and power. The tests were done using an industrially hardened non-rotating UAD system mounted in a CNC turning center. The analysis of variance (ANOVA) was used to find significant parameters of thrust force, temperature, chip morphology and power. Then, for all responses, the optimum drilling parameters that provide desired solutions for all responses were obtained. This was followed by out-of-sample testing to verify the accuracy of the developed models. The results of this study showed that in UAD of aluminum, the minimum values of thrust force and chip size were obtained at low spindle speed, low feed rate and high amplitude. The results also showed that amplitude was not a significant parameter affecting the tool temperature and cannot be used to analyze the effect of ultrasonic vibrations on generated heat during UAD. Instead, the interaction of amplitude and feed rate was significant and should be considered in the analysis. Finally, minimum consumed power, specially at higher amplitudes, can be obtained using high spindle speed and low feed rate.