<p>This study investigates the fatigue crack propagation mechanism of a new high-strength and high-tough Ti–Mo–Cr–V–Nb–Al titanium alloy with three types of microstructures (basketweave structure, lamellar structure, and bimodal structure) through fatigue crack propagation rate tests and fatigue threshold value tests. The resistance of the alloy to fatigue crack propagation was found to be closely correlated with the morphology and distribution of <i>α</i> particles, as evidenced by microscopic examination of fracture surfaces and analysis of crack propagation paths. The primary <i>α</i> particles demonstrated superior resistance to crack propagation compared to the secondary <i>α</i> particles. The basketweave structure showed exceptional resistance to fatigue crack propagation at all stages. The lamellar structure mainly resists long crack propagation during rapid propagation, and its threshold value is the lowest, which makes it easy to produce microcrack propagation. On the contrary, the bimodal structure has the highest threshold value among the three, so its resistance to short crack growth is more excellent, but it has the highest crack growth rate in the higher stress intensity factor range. The <i>α</i> particles in the three microstructures also undergo rotational motion relative to the force axis during fatigue crack propagation, thereby adjusting the uneven stress distribution between <i>α</i>/<i>β</i> phases through slip behavior and further coordinating deformation.</p>