The story opens on the docks of London where Robert Griffin (Jon Hall) returns after five years of memory loss following a diamond field expedition in Africa. Moments later, a newspaper clipping reveals Griffin to be a homicidal maniac who had escaped from a Capetown Asylum.
After acquiring new clothing and a shave, he locates Sir Jasper and Lady Irene Herrick (Lester Matthews and Gale Sondergaard), friends and former partners of the expedition who had left him for dead, to their luxurious mansion and founders of Herrick Mines Ltd., demanding the share of the fortune due him. While talking things over a few drinks, Griffin not only discovers their daughter, Julie (Evelyn Ankers), his former girlfriend, to be engaged to Mark Foster (Alan Curtis), a reporter for the Courier, but finds he's been drugged.
Unable to function, Griffin is escorted out by their butler, Cleghorn (Halliwell Hobbes). Half crazed, Griffin is offered assistance by Herbert Higgins (Leon Errol), a drunkard. Afterwards, Griffin stumbles upon the home of Professor Drury (John Carradine), a scientist who has discovered the formula of invisibility. Witnessing his experiment where Drury's dog and other animals are heard but not seen, Griffin volunteers on becoming Drury's human subject. As an invisible man, Griffin gets his revenge, but in the process, does become what he is accused of being, a homicidal maniac.
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