Abstract: Objective The aim was to solve the bonding difficulties between titanium alloys and stainless steel. Methods Using FeMnNiCr high-entropy alloy and V as a composite interlayer, a high-entropy weld was formed between Ti-4Al-2V titanium alloy and 321 stainless steel, achieving sound formation of the dissimilar metal weld. Results The weld fusion zone primarily consists of FCC solid solution with minor BCC solid solution, where the FeMnNiCr high-entropy alloy combined with V element to form “FeMnNiCrV” quinary high-entropy alloy, effectively suppressing the formation of brittle inter-metallic compounds. Conclusion All tensile specimens fractured in the stainless steel base metal, demonstrating that the high-entropy weld construction resulted in weld zone strength exceeding that of the base metal. Based on the reconstruction of the inter-facial phase structure through high-entropy alloy design, a high-entropy weld was successfully constructed for dissimilar metals, providing a dual optimization approach of “inhibiting brittle phases while strengthening solid solution” for titanium/steel dissimilar metal welding.