Producer Michael Jaffe pursued the rights to Nero Wolfe for decades, starting in the mid-1970s when he and his father Henry Jaffe had negotiated with Rex Stout's estate, only to lose the Zeck trilogy film rights to Paramount Television at that time.

Jaffe deliberately kept the adaptations set in their original 1940s-1950s era rather than modernizing them, arguing that the stories' tonal idiom would not work if updated to a contemporary setting, unlike a previous Paramount adaptation.

The weekly series grew out of the success of a 2000 television film, The Golden Spiders, which drew 3.2 million households and strong critical praise, prompting A&E to greenlight a one-hour drama series afterward.

Saul Rubinek, who played Saul Panzer in the original TV movie The Golden Spiders, switched roles for the series to play reporter Lon Cohen instead.

The show used a distinctive repertory company of around 20-30 actors who returned in different guest roles each week instead of casting new actors for every episode; in one episode, 'Death of a Doxy,' actress Kari Matchett played both her recurring role of Lily Rowan and a separate non-recurring nightclub singer character.

The series was notable for being, as far as its writer knew, the first TV series without a single original script, since every episode was adapted directly from a Rex Stout novel, novella, or short story.

The series was primarily shot in Toronto, with select Manhattan exteriors filmed only for the premiere episode 'The Doorbell Rang,' footage which was then reused in later episodes such as 'Prisoner's Base.'

Production designer Lindsey Hermer-Bell read all of Rex Stout's Nero Wolfe books and companion reference volumes before building the sets, creating a complete floor plan of Wolfe's brownstone to match the books' detailed descriptions, out of concern for scrutiny from devoted fans.

Jaffe/Braunstein Films was among the first production companies to experiment with high-definition video for television, and the entire second season of Nero Wolfe was shot in HD, though home video releases were never issued in that format.

Costume designer Christopher Hargadon sourced many costumes from vintage shops and his personal collection, sometimes disassembling and rebuilding garments with new fabric to get the right color, and estimated his team created at least 1,000 costumes per season.

Composer Michael Small wrote the series' jazzy theme song 'Boss Boogie,' first heard in the titles of 'The Doorbell Rang,' and the score earned a Golden Reel Award nomination for the second-season premiere 'Death of a Doxy.'

Production of the TV series coincided with a resurgence in Rex Stout's book sales three decades after his death, with BookFinder.com reporting in 2003 that the four most-sought-after out-of-print mystery titles were all Nero Wolfe novels.

When A&E cancelled the series in 2002, it posted an unusual 'Important Message' on its website praising the show, and star Timothy Hutton stated the cancellation had nothing to do with ratings since it was the network's highest-rated series at the time.