New York City. November 11, 2000. Sara 'Pez' Pezzini is a New York Homicide Detective for the 11th Precinct. Her childhood best friend, Maria Buzanis, is murdered, and she is certain that Tommy Gallo, one of the city's most dangerous criminals, is the killer. Sara and her partner, Danny Woo, confront Gallo and his hitman, Lorenzo Vespucci. Vespucci knocks Danny down and draws a gun on him. Sara kicks the gun away from Vespucci. Vespucci takes off, and Sara chases after him. They end up at the Midtown Museum where billionaire Kenneth Irons' Joan of Arc collection is exhibited. Sara looks at the Witchblade display, a mysterious sword-like device connected to a iron glove with a red jewel in the wrist area. The blade appears to look back at her. She sees the reflection of a mysterious figure (later identified as Ian Nottingham) from the Witchblade display case and turns around with her gun drawn at him.
Ian, undaunted, says, "Magnificent, isn't it?" Sara tells him that he should go. She finds Vespucci and a shoot-out ensues. A bullet breaks the Witchblade display case and the Witchblade flies out as Sara leaps over a counter to dodge Vespucci's gunfire. The Witchblade ends up on her arm. She instinctively uses the blade to protect herself. One of the bullets deflects off the blade and hits a gas pipe, causing a massive explosion that kills Vespucci. Sara only suffers minor injuries. She looks down at the blade-glove which has turned into a small bracelet with the red jewel in the center. Ian slips away and makes a phone call to someone and tells the unseen person that "she has found it".
The next day, Sara and Danny are at their office. Sara casually puts the bracelet/blade on, unaware of the blade's powers, and looks at the clippings of Maria's death on the wall. She's able to see some of the events on the night of the murder and decides to go back to the crime scene with Danny.
At Gallo's headquarters, Ian arrives and effortlessly takes out all of Gallo's men. He informs Gallo of his boss', Kenneth Irons, decision to sell the Rialto Theatre and invites Gallo to visit the property the next day.
Meanwhile, Jake McCartey, a rookie homicide detective and former professional surfer from San Diego, finds out about Gallo's latest dealing and informs Sara. Sara and Danny go to investigate. They separate in the theater. Sara encounters Ian Nottingham again, but before she has a chance to really interrogate him, one of Gallo's men finds Danny. Gallo tells Sara to come out. Sara asks Ian for help. Ian tells her to use the Witchblade, the bracelet on her wrist. Sara emerges from hiding. Gallo executes Danny right in front of her. When Gallo tries to shoot Sara, the Witchblade morphs into a gauntlet, and she is able to deflect the bullets and protect herself. She ends up in a battle against Gallo's men while Nottingham sits and observes. Gallo and his right hand-man, Drexler, slip out of the theatre. Sara kills all of Gallo's men with the help of the Witchblade.
At the cemetery, after Danny's burial, Danny appears as a ghost. Sara thinks she hallucinating, but eventually accepts it. Danny tells her that she can see him as long as she has the Witchblade bracelet on. He also tells Sara that she comes from a warrior bloodline and that Joe Siri (Sara's Captain, close friend, and her father's partner before he was murdered) will have some answers for her. She later finds out from Joe that she was adopted.
Gallo hires a hitman to kill Sara. The hitman is on the rooftop of the building across from Sara's apartment. Ian appears and knocks him out and kills him just as he was about to pull the trigger and kill Sara. Ian looks through the rifle's telescopic lens and sheds a tear.
With Danny dead, Joe forces her to partner up with the rookie Jake (at Jake's request). Jake finds out more about the Rialto Theatre, including the owner of the theater, Kenneth Irons. Sara learns that Irons owns the Joan of Arc collection and knows Ian Nottingham. Sara goes to Vorschlag Industries (Irons' company) to question Irons about Ian. Sara wants to return the bracelet, but Irons says it belongs to her. Irons offers her his business card and tells her to call anytime.
The next day, Sara meets Irons for a second time to learn more about the Witchblade. Irons tells Sara that only women can wield the blade; that the Witchblade has chosen her and that she must accept it. He explains to her that the scar on the left side of her chest is the mark of the Witchblade ("The circles represent the light and dark powers of the Witchblade"). She doesn't believe him and tells him that the scar is from shrapnel. He then shows him a scar on his right hand, which looks the same as the one she bears. Irons had worn the Witchblade for a brief moment and continues to draw on some of the blade's powers. To control the Witchblade, Irons must control the woman who wields it.
Sara finds Drexler, the snitch, at the Velvet Underground, a nightclub. She forces him to reveal Gallo's whereabouts. She leaves the club to find Gallo. Ian appears out of nowhere and tells Sara that she must spill some of her own blood to fully grasp the Witchblade.
Gallo finds Sara first when he appears in the back seat of her car and forces her to drive into an alley where he tells her that he killed her father in that same alley. Ian appears in armor and distracts Gallo just enough for Sara to escape. Gallo chases after her. Sara and Gallo are in a shoot-out in a subway station. Sara is shot and loses the Witchblade momentarily. She calls out to the blade and regains possession of it. She defeats Gallo and has the opportunity to kill him, but doesn't. Irons is disappointed that she chose not to kill.
The next day, Sara and Jake read from a newspaper article that Gallo was found dead from an apparent suicide. Sara suspects Ian "helped". After looking at the Witchblade bracelet, Sara decides not to confide in Jake or anyone about what really went down with her, and decides to focus more on learning more about the mystical weapon she now wields.