Nearly all of the principal actors and actresses were using their natural accents (be they American, Russian, Czech, Italian, et cetera) with a few notable exceptions. Mark Ryder (Cesare Borgia) and Diarmuid Noyes (Alessandro Farnese) are Irish but used English accents on the show. Even Stanley Weber (Juan Borgia) moderates his French accent, though he doesn't sound as English as his on-screen brother. This is because the series was intended for dubbing into non-English European languages (French, German, et cetera).
Scriptwriter Tom Fontana worked in the Vatican Library and ordered translation from Latin of the papacy documents of that era.
The opening credits show a perfectly round coin, which is an anachronism. The ability to make such coins had not yet been developed.
Isolda Dychauk was 17 years old during the filming of the first season. When asked if she was specifically protected by the production, the actress said, "There was a certain amount of protection. Yet I feel there were more sex scenes in the first season than in the next two. In the meantime, however, no one has to take particularly good care of me. And with the nude scenes, which are never really good, I can cope very well."
Paul Rhys (Leonardo da Vinci) also appeared on Da Vinci's Demons (2013) as Vlad the Impaler, who assisted and antagonized Leonardo da Vinci.