The river rises at sources near Badby, Naseby and Yelvertoft, Northamptonshire, then it flows through arable land, then the industrial landscape of Northampton, Wellingborough and Irthlingborough. After passing through the Cambridgeshire hills and through the cathedral city of Peterborough, the landscape changes to The Fens and their vast, seemingly endless horizons. It flows through Wisbech, then Sutton Bridge in Lincolnshire, and it finally enters the North Sea at The Wash between two towers known as "the lighthouses".
The Nene links the Grand Union Canal to the River Great Ouse, via the Middle Level system.