Freshwater salinisation is a growing problem, yet cross-regional assessments of freshwater salinity status and the impact of agricultural and other sectoral uses are lacking. Here, we assess inland freshwater salinity patterns and evaluate its interactions with irrigation water use, across seven regional river basins (401 river sub-basins) around the world, using long-term (1980-2010) salinity observations. While a limited number of sub-basins show persistent salinity problems, many sub-basins temporarily exceeded safe irrigation water-use thresholds and 57% experience increasing salinisation trends. We further investigate the role of agricultural activities as drivers of salinisation and find common contributions of irrigation-specific activities (irrigation water withdrawals, return flows and irrigated area) in sub-basins of high salinity levels and increasing salinisation trends, compared to regions without salinity issues. Our results stress the need for considering these irrigation-specific drivers when developing management strategies and as a key human component in water quality modelling and assessment. Freshwater salinisation is a growing water quality problem, but impacts and drivers across regional to global scales have been lacking. A new assessment of inter-regional freshwater salinisation demonstrates the importance of irrigation as a driver of salinisation.