When John was 17, he was apprenticed to an ironmonger at Liverpool and became an ironmonger himself about five years later. John probably worked with his father in his foundry (which included a blast furnace) at Bersham in Denbighshire, but in the late 1750s he established, with partners, ironworks at Willey, near Broseley in Shropshire.
Among his products were cannons. These were difficult to cast as the presence of 'honeycombs' (blow holes) was unacceptable to the Board of Ordnance. Traditional cannons had been cast with a core, but in 1774 Wilkinson proposed casting them solid and boring out the core afterwards. Cannons had long been bored to remove imperfections in the casting, but casting them solid and boring out the core after made them much better cannons. Wilksinson also invented and patented in 1775 a new kind of boring machine, that drilled a more precise hole. Unfortunately for him, his invention was not novel, and his patent was eventually repealed.
Another important product was steam engine cylinders. Because his cylinders were so accurately bored, he became the main supplier of these for Boulton & Watt, and also licensed steam engines from them to assist in his ironworks. He also encouraged them to provide steam engines to operate forges, and rotary engines for driving mills, the first rotary engine being installed at Bradley in 1783.
Unknown to Boulton & Watt, Wilkinson was also producing complete "pirated" engines. This was leaked to them by Wilkinson's younger brother, William, after he returned from Europe in the late 1780s and the two had had an argument over their partnership in certain works. Boulton & Watt sued him. As their steam engine patent would soon expire, they established their own Soho Foundry at Smethwick so as to sell complete engines, rather than merely designing them and collecting a royalty.
In 1779 Wilkinson was also a major shareholder in the Iron Bridge, encouraging the other shareholders to make the bridge entirely from iron, though it was Abraham Darby III, rather than he, who actually built it. In 1787 he launched the first iron barge, constructed in Broseley. He patented several other inventions.
By 1796, when he was 68, he was producing about one eighth of Britain's cast iron. He became a titan: very wealthy, and somewhat eccentric.
He left a very large estate in his will (more than ₤130000), which he intended to make his three children the principal heirs, with executors to manage the estate for the children. It was largely dissipated by lawsuits and poor management by 1828. His corpse in the iron coffin was moved several times over the next decades, and is now lost.