| Name | Character | Episodes |
|---|---|---|
| Jeremy Irons | Rodrigo Borgia | 29 |
| Holliday Grainger | Lucrezia Borgia | 29 |
| Joanne Whalley | Vanozza Cattaneo | 29 |
| Sean Harris | Micheletto | 29 |
| François Arnaud | Cesare Borgia | 29 |
| Lotte Verbeek | Giulia Farnese | 20 |
| Colm Feore | Giuliano Della Rovere | 20 |
| Peter Sullivan | Cardinal Ascanio Sforza | 20 |
| Vernon Dobtcheff | Cardinal Versucci | 20 |
| Thure Lindhardt | Rufio | 10 |
| David Oakes | Juan Borgia | 10 |
| Luke Pasqualino | Paolo | 7 |
| Emmanuelle Chriqui | Sancia | 3 |
| Ivan Kaye | Ludovico Sforza | 3 |
| Helen Bradbury | Nanny | 3 |
| Giacomo Gonnella | Battista Colonna | 2 |
| Pilou Asbæk | Paolo Orsini | 1 |
| Callum Turner | Calvino | 1 |
| Elyes Gabel | Cem Sultan | 1 |
| Clive Russell | 1 | |
| Russ Bain | French Soldier 1 | 1 |
| Michelle Ryan | 1 | |
| Jamie Beamish | Siege Overseer | 1 |
| Ivan Kaye | Duke Ludovico Sforza | 1 |
| David Oakes | 1 | |
| Vernon Dobtcheff | 1 | |
| Bosco Hogan | 1 | |
| Luke Allen-Gale | Fredirigo | 1 |
| Prometheus Aleifer | Roberto Orsini | 1 |
| Richard Rifkin | The Penitent | 1 |