The son of a shoemaker from Lewes in Sussex, Mantell was apprenticed to a local surgeon and set up in practice in Lewes in 1812. As the area around Lewes, the South Downs, is rich in Cretaceous deposits, fossil hunting was something of a local pastime and Mantell began collecting fossils in his schooldays.

His interest grew and in 1822, in the area known as the Tillgate Forest, he made his most important find – a large tooth with a worn smooth surface. It obviously belonged to a large herbivore and initially reminded Mantell of an elephant's tooth. However, mammals were unknown in the Cretaceous while reptiles, which were common, did not masticate food. Baffled by his find, Mantell sent his tooth to the great Baron Cuvier in Paris for identification. But Cuvier's judgment that it was the upper incisor of a rhinoceros Mantell knew to be nonsense. He continued to search for an answer and eventually in the Museum of the Royal College of Surgeons he found a smaller but identical tooth belonging to the South American iguana. The tooth, he concluded, came from a lizard after all, a giant toothed lizard he named Iguanadon (iguana tooth).

In 1834 an Iguanadon skeleton was discovered in a Maidstone quarry. Mantell bought the remains for £25 to make, as the joke went, “a famous Mantel-piece.” Mantell also discovered, in 1832, the first armored dinosaur, Hylaeosaurus.

Mantell described his work in his 67 books and memoirs. The best known of these are the once widely read The Geology of South East England (1833) and The Wonders of Geology (1838). His private life, however, fared less well. He moved to Brighton in 1835 in search of patronage and a more affluent practice. He failed on both accounts and sold his vast collection of fossils to the British Museum in 1838 for £4000. Abandoned by his wife and children, he moved to London in 1839, spending most of his time lecturing and writing on geology. He died from an overdose of opium taken to relieve persistent back pain.