Abstract Nucleation control is fundamental to semiconductor deposition, governing when, where and how crystalline materials form. Conventional strategies can regulate nucleation density and, through area-selective growth, confine deposition to designated regions 1–13 . However, they generally do not determine where an individual nucleus forms within the growth regions, leaving even single-nucleation events spatially stochastic and limiting deterministic construction of crystalline materials. Here we report etching-flux-mediated single-centred nucleation of two-dimensional (2D) semiconductors to deterministically localize a single nucleation event. The etching flux released from the barrier suppresses nuclei near the pattern boundary, leaving a single surviving nucleus at the pattern centre, and systematic experiments elucidate the mechanism and establish nucleation design rules for zero, single and multiple nucleation regimes. Etching-flux-mediated single-centred nucleation enables single-crystal molybdenum disulfide growth at the 10-μm scale, field-effect mobilities of up to 117 cm 2 V −1 s −1 and large-area uniformity with process compatibility. This in-plane chemical-flux strategy realizes spatially programmed growth, demonstrating nucleation–growth decoupling for line-shaped single crystals, multiple transistors integrated within a large common crystal, and aligned 2D lateral heterostructures for self-aligned contacts. These capabilities open a path towards advanced 2D electronic integration and expand semiconductor deposition from controlling where materials grow to controlling where and how crystals can begin to form.