Prudence Rutherford, a wealthy socialite from Secret of the Scarlet Hand, recommended Nancy Drew to the Italian Police (the Gdif) to investigate a series of art thefts happening in Venice. A Crime Syndicate is actually responsible for the thefts, using the names of the commedia dell'arte characters. Nancy is sent to spy on the ring and discover who is Il Dottore, the ringleader of the crimes.
- Colin Baxter
A handsome British art restorer. He is restoring Ca' Nascosta for a small amount of money. He seems to have a crush on Nancy, and is always giving her compliments. Could he be working for so cheap because he has a part-time job as Il Dottore?
- La Contessa Margherita Fauberg
A very wealthy woman, owner of Ca' Nascosta, she inherited a large sum of money when her husband died. Could her large spending cause her to need to steal to pay off debts?
- Helena Berg
A journalist and a specialist on reporting high profile crimes, she is also an expert on the failures and successes of crime rings. She does not condone what the phantom is doing, but she finds it so fascinating. Does she have her own agenda as Il Dottore?
- Enrico Tazza
Owner of the Casa dei Giochi, or House of Games, he was originally a member of the Machiano Crime Syndicate. Nancy has to beat him at Scopa in order to talk to him. He wears a mask.
- Antonio Fango
A prime suspect on the case. Nancy's assignment to is to perform surveillance on him, and she never gets to talk to him. Could he be the one that's been stealing art? After all, he installed the security systems in the places where the art was recently stolen.
- Sophia Leporace
An agent for the GDiF. She helps Nancy locate the "Phantom" and gives her the assignments she needs to complete via her PDA.
Nancy's boyfriend who always worries when she is on a case, yet he helps her out nonetheless. Ned gave Nancy a beautiful locket before she got on the plane for Venice, Italy. Ned is staying at Bayport with Joe Hardy (Frank went snow camping) and Joe decided to "tinker" with his car. He can be called for hints.
- Joe Hardy
One of the Hardy Boys Detectives. Ned is staying with him while Nancy is in Italy. Joe likes to "tinker" with things... especially Ned's car. He can also be called for hints via Ned's phone number when Ned is trying test his car.
- Prudence Rutherford
She sent Nancy to Venice to solve the case, retrieve all the stolen art, and capture the "Phantom". She loves money, writing her memoirs, and her dog Ginger. Prudence referred Nancy to the Italian police after Nancy helped her retrieve a stolen item in a previous game.
- Samantha Quick
She is a mysterious character who Nancy pretends to be to get inside the Casa dei Giochi. She calls Nancy to threaten her and warns Nancy against impersonating her again.
- Nico Petit
The Gdif suspect him of being the Phantom. He works for Enrico Tazza.
A part of Il Dottore's gang. She sent Samantha(who Nancy disguises) the lock pick kit to get inside the Zattere. Her name in the gang is Scaramuccia. You may talk to her via chatting with her using Fango's laptop.
Like all Nancy Drew games, there are fatal accidents you can make. Unlike the other games , when you make a mistake, it will give you a funny 'Good News' and funny 'Bad News' before giving you the choice to try again. (This little perk happens in all games after this.)
- Inputting the incorrect combination at Zattere
- Banging on the locked gate at Zattere multiple times
- Being stung by too many bees when picking flowers
- Getting caught snooping in Fango's office
- Not avoiding the falling urn
- Failing the stakeout
- Walking in the dark with no flashlight and falling into a hole
- Not getting out of the water trap in time
- Letting the culprit get away
- Picking the lock and entering Fango's office while he's in there
- Nancy Drew - Lani Minella
- Helena Berg - Adrienne MacIain
- La Contessa Margherita Fauberg - Gin Hammond
- Colin Baxter - Jonah von Spreecken
- Sophia Leporace - Angela Mills
- Enrico Tazza - Bruce Milligan
- Fausto - R. Riedl
- Ned Nickerson - Scott Carty
- Joe Hardy - Rob Jones
- Prudence Rutherford - Simoune Choule
- 'Samantha Quick' was suggested as Nancy's stage name in The Final Scene
- The name Nancy receives while dancing at the nightclub, Punchy LaRue, is the name of the person who formerly voiced Bess Marvin. Punchy LaRue is also found on the plaque to the left of Joanna's office in Secret of the Scarlet Hand.
- While listening in on one of Margherita's conversations, she mentions talking to Red Knott, who is in Ghost Dogs of Moon Lake.
- While also talking to Margherita, she makes a reference to the flowers near where she is sunbathing. She says Prudence Rutherford got them at the Hilihili Research Center in Hawaii. The Hilihili Research Center is one of the places in The Creature of Kapu Cave.
- While talking to Prudence Rutherford, she mentions a "Minette original" referring to Minette and her fashion industry from Danger By Design.
- While looking in Helena's book you find a reference of Sonny Joon who is mention in past games aka Danger By Design and Secret of the Scarlet Hand.
- Also, while reading the notes on Sonny Joon, Helena mentions Sonny is headed for the Caribbean. This is a reference to the upcoming Ransom of the Seven Ships.
- At the end of the game after the credits there are bloopers.
- One of the postcards sitting on the dresser mentions someone named "Nina", followed by the words 99 Luftballoons. Nena is a famous German singer, and "99 Luftballoons" is one of her songs.
- The skeleton mask you can buy in the costume shop is the same that is worn by the Jolly Rogers club in Legend of the Crystal Skull.
- The toy robot found in Antonio Fango's File Cabinet looks and acts just like the robot in Josaiah Crowley's house in Secret of the Old Clock.
- When you're looking through Margherita's letter when she's not there, she will mention that she sat down with the Ambassador of Fredonia. Fredonia is the country of Yanni Volkstaia in White Wolf of Icicle Creek.
- When going through the garbage bin outside the Casa dei Giochi, you can see different objects from past Nancy Drew games like the snow shoe is from White Wolf of Icicle Creek and the horse head named Glory is from The Haunted Carousel.
- When looking in Nancy's make-up bag, you can see several references to real cosmetics brands such as Supersmile, Bobbi Brown Cosmetics, and M.A.C. Cosmetics. It is not known if these are direct product placements seeing as though the labels are slightly blurred.
- In Danger By Design, there is a baby head that you can buy from the merchants. In the costume shop, there is a similar mask almost the same as the doll.
In the bloopers of this game "Nancy" looks at the Canal and an aligator/crocodile appears and "Nancy" says "Hi Bernie" a refence to the alligator/crocodile in Legend of the Crystal Skull the 17th game and the one just before this game.
This is the first game in the series
- with bloopers after the credits.
- to show a portion of the game's ending at the beginning.
- Ca' Nascosta is Italian for "hidden house".
- Margherita is the Italian word for "daisy".
- Club Micio means "Kitty Cat Club" in Italian.
- The owner of Club Micio tells Nancy that her stage name should be "Punchy LaRue". Punchy LaRue was the voice of Bess Marvin in Nancy Drew: The Final Scene.
- One of Helena's postcards is addressed to Nina at 99 Luftbaloons. 99 Luftballons is a German protest song by the band Nena.
- The binary code in Antonio's office says, "I love cute little fuzzy animals."
- You can get an easter egg by picking the lock of the door to the left of Colin's workplace.
- If you make a gelato in the Rialto Market with red on the bottom, white in the middle, and green on the top, (the colors of the Italian flag) you can get an easter egg.