He is first heard of as the author of a pamphlet on the Three Miseries of Barbary, which dates from 1606. He then collaborated in 1607 with William Rowley and John Day in The Travels of the Three English Brothers, a dramatisation of the real-life adventures of the Sherley brothers.
In the same year Wilkins wrote The Miseries of Enforced Marriage. This play is based on the story of Walter Calverley, whose identity is thinly disguised under the name of "Scarborough." This man had killed his two children and had attempted to murder his wife. The play originally had a tragic ending, but as played in 1607 ended in comedy, and the story stopped short before the catastrophe, perhaps because of objections raised by Mrs Calverley's family, the Cobhams. The crime itself is dealt with in a short play, A Yorkshire Tragedy of uncertain authorship.
Wilkins was associated with the King's Men, and their chief playwright William Shakespeare. Shakespeare and Wilkins were both witnesses in the case of Bellott v. Mountjoy in 1612; in his deposition he described himself as a 'victualler', but he was also known to the authorities as a procurer or pimp, and had been in court before on several occasions, mainly for accusations of violence against women. A number of studies have attributed to Wilkins a share in Shakespeare's Pericles, Prince of Tyre (which does not appear in Shakespeare's First Folio, but was published only in a textually corrupt quarto). This may have been collaboration, or perhaps Wilkins was the original author of Pericles and Shakespeare remodelled it, or vice versa. However it may be, Wilkins published in 1608 a novel entitled The Painful Adventures of Pericles, Prynce of Tyre, being the true history of Pericles as it was lately presented by ... John Gower, which sometimes follows the play very closely. The editors of the 1986 Oxford Edition of Shakespeare make the assumption that Wilkins was the co-author of Pericles and draw heavily upon The Painful Adventures in their controversial reconstructed text of the play.