Interface modulation of nickel phosphide (Ni2P) to produce an optimal catalytic activation barrier has been considered a promising approach to enhance the hydrogen production activity via water splitting. Herein, heteronuclei‐mediated in situ growth of hollow Ni2P nanospheres on a surface defect‐engineered titanium carbide (Ti3C2Tx) MXene showing high electrochemical activity for the hydrogen evolution reaction (HER) is demonstrated. The heteronucleation drives intrinsic strain in hexagonal Ni2P with an observable distortion at the Ni2P@Ti3C2Tx MXene heterointerface, which leads to charge redistribution and improved charge transfer at the interface between the two components. The strain at the Ni2P@Ti3C2Tx MXene heterointerface significantly boosts the electrochemical catalytic activities and stability toward HER in an acidic medium via a combination between experimental results and theoretical calculations. In a 0.5 m H2SO4 electrolyte, the Ni2P@Ti3C2Tx MXene hybrid shows excellent HER catalytic performance, requiring an overpotential of 123.6 mV to achieve 10 mA cm−2 with a Tafel slope of 39 mV dec−1 and impressive durability over 24 h operation. This approach presents a significant potential to rationally design advanced catalysts coupled with 2D materials and transition metal‐based compounds for state‐of‐the‐art high efficiency energy conversions.