Bidding on the original cover art for 1939's Action Comics #15, which features the fifth appearance of Superman, stands at $47,000 at Heritage Auctions.
The sale is due to take place in New York on February 20-22.
Created by legendary illustrator Fred Guardineer (1913-2002), the work shows Superman rescuing a submariner.
Guardineer was among the first artists on the Action Comics roster, creating Zatara the magician for the first issue - a character that remains a fixture in the DC canon.
In November last year a piece of cover art by Curt Swan for Action Comics #309, which featured JFK and was coincidentally released soon after his assassination, made $112,000 at Hake's Americana and Collectibles.
Amazing Fantasy #15 is another highlight of the sale, currently at $30,000.
The 1962 comic features the first appearance of Spider-Man, a character who went on to become a part of pop cultural history.
The lot, graded CGC VF/NM 9.0, is one of only a handful remaining in this condition - making it an exceptionally desirable piece.
In 2011 another copy, graded CGC 9.6, made $1.1m in a private sale.
A piece of original artwork for page six of Frank Miller and Klaus Janson's The Dark Knight Returns #2 (1986) stands at $25,000.
Last year the cover art for Miller's classic work sold for $478,500.
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