Rome was originally pitched to HBO by William J. MacDonald and John Milius as a miniseries, but the network expanded it into a full-fledged series.

In 2002, HBO and the BBC agreed to co-produce the series with a budget of $100–110 million for twelve one-hour episodes, HBO contributing $85 million and the BBC $15 million; it was the largest co-produced series with the American film market in the BBC's history.

The filmmakers deliberately avoided the polished 'Hollyrome' look of clean marble and pressed togas seen in other films, aiming instead for a gritty, realistic depiction of ancient Rome.

The series was filmed between March 2004 and May 2005 at Cinecittà Studios in Rome using six sound stages, with elaborate back-lot sets recreating ancient Rome, involving an international crew of 350 plus over 50 local Italian interns.

A significant portion of the massive Cinecittà set built for the show was destroyed by a fire in 2007, which occurred after filming of the second season had wrapped.

Part of the surviving Rome set was later reused in late 2007 by the crew of Doctor Who for the fourth-season episode 'The Fires of Pompeii'.

According to the Season 1 DVD commentary, many background performers were playing their real-life professions on screen, such as an actor who portrayed a street butcher and was in fact a genuine butcher.

The show was shot on Panasonic SDX 900 DVCPro 50 camcorders in widescreen progressive scan at 25 frames/s; producer Mark Hedgecoe chose this standard-definition format because it avoided needing an external monitor for focusing, speeding up shooting and giving a filmic feel suited to the gritty tone.

For the BBC broadcast, the first three episodes (all directed by Michael Apted) were re-edited into two episodes; the BBC said this was because British audiences knew Roman history better, but Apted claimed it was actually done to boost ratings by emphasizing sex and violence scenes, and he only learned of the cuts by accident from an actor.

In Italy, strong language was removed in dubbing and explicit sex and violence scenes were replaced with alternate 'safe' versions shot specifically for the Italian market during production; the uncensored version only aired in Italy on Rai 4 starting September 2009.

Composer Jeff Beal was invited to audition for the show after completing work on HBO's Carnivàle, and based on a short edit of season 1 episode 7 he wrote a demo score using live instruments from across the ancient Roman world to achieve the gritty pre-Christian feel the producers wanted.

HBO chairman Chris Albrecht announced in July 2006 that season two would be the show's last because the series, developed under a two-year contract with the BBC, was too expensive to extend; co-creator Bruno Heller said he learned of the cancellation halfway through writing season two and had to telescope the planned third and fourth seasons (set in Egypt) into the second.

Series historical consultant Jonathan Stamp identified the historical figure Clodia, rather than the little-documented real Atia, as the primary basis for Polly Walker's character Atia of the Julii.

The pilot episode 'The Stolen Eagle' won a Visual Effects Society award and a Directors Guild of America award for Michael Apted, and the show later won four Primetime Emmy Awards for the episodes 'Caesarion,' 'Triumph,' 'Kalends of February,' and 'Stealing from Saturn.'