Esopus featured content from a wide variety of creative disciplines, including artists' projects, critical writing, fiction, poetry, visual essays, interviews, and music—all presented in an unmediated format, with minimal editorial framing and no advertising.

Contents also regularly include essays on process by creative professionals such as Mad Men creator Matthew Weiner, choreographer Christopher Wheeldon, translator Ann Goldstein and cruciverbalist David Quarfoot.

Esopus has featured essays by Karl Ove Knausgaard and Francine Prose; scripts by Stephen Adly Guirgis, Christopher Durang, and Hampton Fancher; and fiction by a dozen previously unpublished authors (many of whom, such as Vivien Shotwell and Stuart Nadler, have gone on to publish novels with major houses).

Other contents included portfolios debuting the work of undiscovered artists such as Mark Hogancamp,[2] Alex Masket, and Samuel Varkovitsky; commentary by museum guards about the artworks they oversee; a series called "100 Frames" that features still images from films by Chantal Akerman, Claire Denis, Charles Burnett, David Lynch, and many others; and a CD of new music in every issue commissioned according to a particular theme.

Exhibitions included "Ray and Bob Box", "Picturing Marwencol: Photographs by Mark Hogancamp", and "Bryan Nash Gill: What Was Will Be Again"; and events ranged from concerts by Sam Amidon and Nina Nastasia to a screening with the late experimental filmmaker Peter Hutton.

Esopus was called "a thing of lavish, eccentric beauty, less flipped through than stared at, forcing readers to reconcile their expectations of what a magazine is with the strange artifact in their laps," by The New York Times's David Carr.