The Andes region has an exceptional record of high-altitude settlements integrated within widespread regional chains of mobility and exchange. The Sierra de Aconquija (NW Argentina, south-central Andes) is an effective climatic barrier that has afforded an enduring indigenous approach to land use, mobility, and exchange over millennia. Despite this rich history, the Sierra has been largely considered marginal in pre-Columbian regional cultural developments. Today, the expansion of extractive industries threatens the region’s heritage and the sustainable futures of local communities. Innovative, integrative methodologies are needed for landscape characterisation, heritage assessment, and sustainable policy development. Building on earlier work, we undertook the first comprehensive mapping of archaeological features over 3800 sq. km of the Sierra using interpreter-led assessment of commercial and open-access satellite imagery and DSM data, to verify earlier assumptions and to identify previously unnoticed trends in the aggregation, distribution, and connectivity of archaeological features. The mapping identified 6794 features distributed unevenly but with clear tendencies towards maximising topographic, ecologic, and connectivity advantages expressed consistently across the study area. The outcomes confirm the important role the Sierra had in pre-Hispanic times, highlighting the significance of ancient indigenous practices for the sustainability of vulnerable upland landscapes both in the Andes and worldwide.