In this study, an innovative method was applied for bonding Zircaloy-4 to stabilized austenitic stainless steel 321 using an active titanium interlayer. Specimens were joined by partial transient liquid phase diffusion bonding method in a vacuum furnace at different temperatures under 1 MPa dynamic pressure of contact. The influence of different bonding temperatures on the microstructure, microindentation hardness, joint strength, and interlayer thickness has been studied. Additionally, a simple numerical model was developed to predict the evolution of interlayer during partial transient liquid phase diffusion bonding. Diffusion of Fe, Cr, Ni, and Zr has been investigated by scanning electron microscopy examinations and energy dispersive spectroscopy elemental analyses. Results showed that control of heating and cooling rate and 20 min soaking at 1223 K produces a perfect joint. However, solid state diffusion of the melting point depressant elements into the joint metal causes the solid/liquid interface to advance until the joint is solidified. The tensile strength values of all bonded specimens were found around 480–670 MPa. Energy dispersive spectroscopy studies indicated that the melting occurred along the interface of bonded specimens as a result of transfer of atoms between the interlayer and the matrix during bonding. The evolution of interlayer film thickness indicates a good agreement between the calculation and experimental measurement. This technique provides a reliable method of bonding zirconium alloy to stainless steel.