Local water use is significantly affected by distant economies through global supply chains. Ghana is one of the largest trade hubs in sub-Saharan Africa, and large amounts of Ghana's water use are embodied in international exports. Previous studies have made efforts to evaluate direct water use in Ghana but overlooked nations and sectors indirectly driving Ghana's water use. This study explored global supply chain drivers of Ghana's water use during 2012–2021, based on the global environmentally extended multi-regional input-output (EE-MRIO) model. Results revealed that the total water use of Ghana was 9790 million m3 (Mm3) during this period. About 39% of Ghana's water use is attributed to foreign consumption and more than 12% is driven by the US and the UK. The domestic and foreign demand for the products of the “spices and pharmaceutical crops” sector is an important sectoral driver of Ghana's water use. From the supply side, domestic primary inputs account for 93.1% of the national water use whereas only 6.9% is attributed to foreign primary inputs. The domestic sectoral suppliers are mainly the “spices, and pharmaceutical crops” and “wholesale and retail trade” sectors. The critical foreign nations from the supply side are China and Cote d’Ivoire, enabling 88.5 Mm3 and 59.0 Mm3 of Ghana's water use respectively. Demand-side initiatives (i.e., consumer tax and education) and supply-side measures (i.e., efficient water use compliance) should be integrated with existing production-side policies to regulate sub-Saharan Africa's water use.