<p>The rapid development and production of electric vehicles, along with the growing demand for advanced energy storage systems such as modern batteries, have significantly increased the importance of ultrasonic metal welding as a joining method. In this study, dissimilar ultrasonic welding of aluminum alloy AA1050 and high-purity copper (99.9%) coated with nickel was investigated. The effects of key process parameters—welding time, pressure, and amplitude—on the mechanical strength of the joint were examined and optimized using design of experiments (DOE) and the response surface method (RSM). To evaluate the joint strength, tensile-shear tests were conducted, accompanied by microscopic examination of the weld cross-section and the fracture surfaces. The DOE results indicated that welding time, pressure, and the second-order term of ultrasonic amplitude are the most influential parameters positively affecting the joint strength. The maximum tensile shear strength obtained was 869.4 N. With an increase in welding time, the effective weld thickness improved significantly—from 55.2% for a 0.2-s weld time to 34% at 1&#xa0;s. Microstructural analysis at the weld interface revealed that interfacial diffusion and mechanical interlocking are the dominant welding mechanisms. The effective thickness and bond density of weld were identified as the most critical microstructural factors influencing the joint strength. Moreover, compared to the direct welding of dissimilar aluminum and copper, the presence of the nickel coating enhanced the joint strength at shorter welding times and across a broader range of parameters—leading to an approximately 5.5% increase in maximum mechanical strength.</p>