Abstract Human mobility is strongly associated with the spread of SARS-CoV-2 via air travel on an international scale, and with population mixing and the number of people moving between locations on a local scale. However, these conclusions are drawn mostly from observations in the context of the global north where international and domestic connectivity is heavily influenced by the air travel network; scenarios where land-based mobility can also dominate viral spread remain understudied. Furthermore, research on the effects of non-pharmaceutical interventions (NPIs) has mostly focused on national- or regional-scale implementations, leaving gaps in our understanding of the potential benefits of implementing NPIs at higher granularity. Here, we use Chile as a model to explore the role of human mobility on disease spread within the global south; the country implemented a systematic genomic surveillance program and NPIs at a very high spatial granularity. We combine viral genomic data, anonymised human mobility data from mobile phones and official records of international travellers entering the country to characterise the routes of importation of different variants, the relative contributions of airport and land border importations and the real-time impact of the country’s mobility network on the diffusion of SARS-CoV-2. The introduction of variants which are dominant in neighbouring countries (and not detected through airport genomic surveillance) is predicted by land border crossings and not by air travellers, and the strength of connectivity between comunas (Chile’s lowest administrative divisions) predicts the time of arrival of imported lineages to new locations. A higher stringency of local NPIs was also associated with fewer domestic viral importations. Our analysis sheds light on the drivers of emerging respiratory infectious disease spread outside of air travel, and on the consequences of disrupting regular movement patterns at lower spatial scales.