The series was devised by Joe Quesada and Axel Alonso shortly after they became Marvel Comics' editor-in-chief and senior editor respectively.

However, Alonso's contacts from his work with DC Comics and their Vertigo imprint attracted a number of acclaimed creators to the series, including Darwyn Cooke, Garth Ennis, Duncan Fegredo, Jim Mahfood, Ted McKeever, Peter Milligan, Paul Pope and Greg Rucka.

[1][4][5] While the series was nominally set in the Marvel Universe, the creative teams were given considerably leeway in terms of how strongly they adhered to continuity.

[9] In an overall series review before #20, Wizard rated Spider-Man's Tangled Web as 'B-', noting the format was "both the strength and weakness" of the title.

[18] and was named as one of the '10 Weirdest Spider-Man Comics' by Tilt Magazine, writer David Gelmini describing it as "an enjoyably offbeat insight into the psyche of the most imbecilic member of the Sinister Six".