<p>Fatigue crack growth at the welded seam is a primary cause of failure in titanium alloy welded structures. However, the influence of crack orientation relative to the weld interface on fatigue performance remains insufficiently understood. This study systematically investigates the effects of crack location and the crack-interface angle on the fracture toughness and fatigue crack growth behavior of TC4 titanium alloy joints produced by argon arc welding. The results show that the joint exhibits optimal fracture toughness and the longest fatigue crack propagation life when the crack propagates perpendicular to the weld interface (<i>γ</i> = 90°), achieving a 43% increase in total fatigue life compared with the parallel orientation (<i>γ</i> = 0°). The interface shielding mechanism is revealed through crack-tip closure effects, plastic zone contraction, and microstructural discontinuity across the weld interface. A modified Paris model incorporating a shielding factor <i>S</i> is proposed, which successfully collapses all experimental data onto a single master curve (<InlineEquation ID="IEq1"> <EquationSource Format="TEX">\({R}^{2}=0.961\)</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <msup> <mrow> <mi>R</mi> </mrow> <mn>2</mn> </msup> <mo>=</mo> <mn>0.961</mn> </mrow> </math></EquationSource> </InlineEquation>). This study provides a quantitative understanding of the interface shielding mechanism and offers a practical prediction tool for the safety design and life assessment of titanium alloy welded structures.</p>