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Healing of the tendon-to-bone interface remains a challenge in clinical practice due to its unique gradient structure. Despite substantial efforts to reproducing the transitional structure from mineralized to nonmineralized tissue, successful regeneration of tendon-to-bone interface through tissue engineering approaches remains rare. To maximally simulate the four distinct zones of the tendon-to-bone interface, a novel three-dimensional (3D) hydroxyapatite (HA) gradient scaffold with spatial mineral distribution is implemented through a combined strategy of electrospinning and traditional textile manufacturing. Our results showed that the scaffold allows sustained release of Ca ions from each segment in a gradient manner. Besides, this scaffold is structurally anisotropic with excellent mechanical properties. In vitro study demonstrated that the mineralized segments boosted the proliferation of mouse embryo osteoblast precursor cells (MC3T3-E1) cells and promoted osteogenic differentiation of rat bone marrow stem cells (rBMSCs), while nonmineralized segment improved the tenocytes differentiation of rBMSCs. Moreover, the HA gradient scaffold was able to spatially guide the differentiation of rBMSCs, leading to the formation of neotissue with structural, biochemical, and biomechanical characteristics similar to that of the tendon-bone insertion site. Overall, this study introduces an approach to inducing targeted and localized stem cell differentiation for tissue engineering applications, and the HA gradient scaffold holds enormous potential for tendon-to-bone tissue regeneration.