After the First English Civil War the family returned to London and Moxon and his older brother, James, started a printing business which specialized in the publication of Puritan texts, with the notable exception of A Book of Drawing, Limning, Washing or Colouring of Mapps and Prints of 1647 which was produced for Thomas Jenner, a seller of maps.

In 1652, Moxon visited Amsterdam and commissioned the engraving of globe-printing plates, and by the end of the year was selling large celestial and terrestrial globes in a new business venture.

He specialised in the printing of maps and charts, and in the production of globes, and mathematical instruments made of paper.

It was completed in two volumes: the first giving instructions on metalworking, woodworking, brick-laying and sundial-construction; and the second (issued 1683–1684) providing a detailed series of instructions for printers, including typefounding, composition, press-work etc., which have given printing historians much (probably idealised) information on the working practices of hand-press period printing-houses.

His shop at this time was on Ludgate Hill; afterwards, in 1683, it was "on the west side of Fleet Ditch", but always "at the sign of Atlas".