Isaac was the son of a Dissenter, Edward Maddox, stationer of London. He was orphaned at an early age, and brought up by an aunt who sent him to a charity school before apprenticing him to a pastry cook. However, assisted by an uncle, he resigned his apprenticeship and was tutored by Rev Hay, vicar of St Stephen Coleman Street. As a practising Dissenter, Maddox was given a grant from the Presbyterian Fund to study for the Dissenting ministry at the University of Edinburgh. Here he befriended John Horsley, who later became the father of Samuel Horsley, who at that time was also destined for the Dissenting ministry. He was awarded MA in January 1722/3.