Bioavailable Sr and detrital Nd isotopes are important tools for archaeological provenance. To apply Sr and Nd isotopes for provenance, regional isotope databases and baselines are generally needed. For the vast Silk Road regions of Mesopotamia, Iran, and Central Asia, detailed isotopic distribution patterns essential for determining provenance may not become available in the short term due to the severe deficiency of available data. In the present work, we investigate the geo-environmental factors controlling the Sr and Nd isotopic signatures and use published data from archaeology and Earth sciences, selected by rigorous criteria, to construct the first large-scale, semi-quantitative Sr–Nd isotope baseline for these Silk Road regions. Three isotopic zones are proposed for Central Asia: CA-1 (mountains), εNd < −7.5, 87Sr/86Sr > 0.7095; CA-2 (deserts), εNd = −5 to −2, 87Sr/86Sr ∼ 0.709; CA-3 (loess), εNd = −5 to −2, 87Sr/86Sr > 0.710. General isotopic signatures are suggested for Iran: εNd = −8 to −4, 87Sr/86Sr = 0.7075–0.7090. Three isotopic zones are proposed for Mesopotamia: MP-1 (floodplain and foothill), εNd = −6.5 to −4 (putative extended range MP-1N, εNd = −8 to −6), 87Sr/86Sr = 0.7080–0.7085; MP-2 (deserts), εNd < −8, 87Sr/86Sr > 0.7085; MP-3 (Syrian Euphrates), εNd = −5.5 to −2, 87Sr/86Sr = 0.7080–0.7085. Within the limitation of available data, these ranges indicate the overall trend of bioavailable Sr and detrital Nd isotopic signatures for each isotopic zone, which are controlled by their geological context, climate (e.g., precipitation), and various Earth surface processes (e.g., riverine versus aeolian transport). This baseline can be used as an essential guide for geochemical contexts to suggest or verify the provenance of plant-ash glass, serving as part of an integrative Sr–Nd isotopic approach. We illustrate the potential of this approach using two case studies. By investigating the isotopic compositions of Mesopotamian plant-ash glass, we suggest possible northern Mesopotamian origins for plant ash and silica raw materials used for Mesopotamian glass-making. By reassessing medieval plant-ash glass from San Lorenzo, Italy, we propose diverse origins including Central Asia and Mesopotamia. Additionally, as part of this isotopic approach, by examining the Nd isotope mixing lines in the context provided by the Nd isotope baseline, we reveal the occurrence of glass recycling for Islamic plant-ash glass from different production zones in association with a westward spread from Mesopotamia to the Eastern Mediterranean metropolises.