Eshleman has been translating since the early 1960s. He is the recipient (with José Rubia Barcia) of the National Book Award in 1979 for his co-translation of César Vallejo's Complete Posthumous Poetry. He has also translated books by Aimé Césaire (with Annette Smith), Pablo Neruda, Antonin Artaud, Vladimir Holan, Michel Deguy and Bernard Bador. In 2006, a translation of The Complete Poetry of Cesar Vallejo, with an introduction by Mario Vargas Llosa, was published to much acclaim, won the 2008 Harold Morton Landon Translation Award from the Academy of American Poets, and was shortlisted for the 2008 International Griffin Poetry Prize.

Eshleman founded and edited two of the most seminal and highly-regarded literary magazines of the period. Twenty issues of Caterpillar appeared between 1967 and 1973. In 1981, while Dreyfuss Poet in Residence at the California Institute of Technology, Eshleman founded Sulfur magazine. Forty-six issues appeared between 1981 and 2000, the year its final issue went to press. Eshleman describes his experience with the journal in an interview which appeared in an issue of Samizdat .

Sometimes he is mentioned in the company of the "ethno-poeticists" associated with Jerome Rothenberg, including: Armand Schwerner, Rochelle Owens, Kenneth Irby, Robert Kelly, Jed Rasula, Gustaf Sobin, and John Taggart. Over the course of his life, his work have been published in over 500 literary magazines and newspapers, and he has given readings at more than 200 universities. He is now Professor Emeritus at Eastern Michigan University.

In the fall of 2005, Clayton and his wife Caryl were in residence at the Rockefeller Study Center at Bellagio on Lake Como, Italy, where he studied Hieronymus Bosch's "The Garden of Earthly Delights" and wrote a 67 page work on the triptych in poetry and prose, "The Paradise of Alchemical Foreplay." For over thirty years, Clayton Eshleman has studied Ice Age cave art of southwestern France. In June 2006, the Eshlemans plan to be in France to lead their 8th cave tour to the painted/engraved Ice Age caves for the Ringling College of Art and Design.