The first season of the Canadian science fiction–fantasy television series Sanctuary premiered on the Sci Fi Channel in the United States on October 3, 2008, and concluded on ITV4 in the United Kingdom on January 5, 2009, after 13 episodes. It follows the actions of a secret organization known as the Sanctuary, who track down a series of creatures known as abnormals, and then bring them to the Sanctuary for refuge. The main story arc of the season involves the Sanctuary working against the Cabal, an organization who seek to control all abnormals for their own gain.

Initially an eight-part web series, Sanctuary was successful enough for Sci Fi to commission a television series. Series creator and head writer Damian Kindler hired Sam Egan, and the two wrote all the episodes and composed the season-long storyline. Many episodes had been written throughout the 2007 Christmas season before the season was green-lit. Principal photography started in May 2008. It was the first instance in North American television where RED cameras were used. Most of the season was filmed using green screen in a warehouse in Burnaby, British Columbia, though there are instances throughout that were filmed on location, including the Riverview Hospital in Coquitlam and the North Shore Mountains outside Vancouver. Anthem Visual Effects produced the season's visual effects. The virtual sets meant that they produced around 400 visual effects per episode. Other forms of special effects, including prosthetics, were used to present the abnormals. The first season was budgeted at an estimated $21 million.

Sanctuary's first season aired in over 50 countries worldwide. The season premiere drew the largest audience with 2.7 million viewers, the highest rated Sci Fi premiere since Eureka in July 2006. Including time-shifted viewing, the season was seen by an average of 2.35 million viewers per episode; the ratings success allowed Sci Fi to renew Sanctuary for a second season. Critical reactions of the season were mixed. Some reviewers noted that, although the first six episodes were "hit and miss", they liked the later episodes. In total, it won five awards: one Gemini and four Leos. The first season was released on a four-disc set on DVD and Blu-ray Disc on September 9, 2009, in Region 4, September 15 in Region 1, and October 15 in Region 2.

The first season consists of four principal cast members. Amanda Tapping plays series protagonist Helen Magnus, a 157-year-old English scientist who runs the Sanctuary network. Tapping darkened her hair color for the role. Robin Dunne plays Will Zimmerman, a former forensic psychiatrist and then Magnus' protégé since the pilot. Damian Kindler noted that Dunne's portrayal as Zimmerman differed vastly between the webisodes and the first season, often joking that Zimmerman was played by two different Dunnes. Emilie Ullerup plays Ashley, Magnus' daughter. Ullerup enjoyed working with the cast during the first season. She felt that Tapping was "such a teacher" to her, and that it had been "such a treat" working with Tapping as a young and new actress.

Christopher Heyerdahl plays two characters: Bigfoot, an abnormal who works in the Sanctuary, and John Druitt, Magnus' former fiancé and father to Ashley. As Bigfoot, Heyerdahl had to wear prosthetics. Tapping believed that Heyerdahl "has this incredible gift wearing prosthetics and acting through them and creating real humanity, and he does it with Bigfoot." Ullerup also felt nervous, yet excited playing every scene with Heyerdahl when he plays Druitt.

Ryan Robbins plays Henry Foss, who runs the Sanctuary's computer and security systems. The producers wanted Henry to set a lighter tone to the series and add "goofy and fun" humor, including in somewhat dire situations. The producers cast Robbins, and were pleased with his performance. Chuck Campbell plays "two-faced guy", a character with another face at the back of his head. The back face was accomplished using visual effects. Panou plays Sylvio, an associate of Ashley's. The character was originally named Ernie and was played by director Peter DeLuise in the webisodes, but he was unavailable to reshoot his scenes for the season premiere. Jonathon Young stars as Nikola Tesla. Heyerdahl suggested Young to the producers, who ended up being highly impressed by his performance. Young also played Tesla in a one-man show before appearing in the series. Whilst filming the second part of "Revelations", Young's scenes in the underground city were filmed first, as he was scheduled for another play while the episode was shot.

At the time of filming "The Five", the actors who played Watson and Griffin had not been cast yet. The producers would later cast Peter Wingfield as Watson. According to Amanda Tapping, casting Wingfield was "so easy" as "he has this sensibility about him, much like [Christopher Heyerdahl] does." While filming his scenes, Wingfield did not want his exoskeleton prop to be removed between takes, as he wanted to stay in character. When the producers conceived Clara Griffin, the granddaughter of Nigel Griffin, they were looking for a young local actress to play the part who would look like a potential love interest to Will Zimmerman. Christine Chatelain would later play the part after she was recommended by Dunne, as they had worked together before.

When Adrien Dorval auditioned for his part on "Kush", Kindler did not like his performance, but Wood did, as he believed the actor's performance was perfect for a character who was stranded on a plane. For the same episode, Sarah Strange and Thai-Hoa Lee had to learn how to speak Standard Tibetan phonetically a week in advance of filming. Katharine Isabelle guest starred in "Nubbins" as Sophie. While filming her scenes, Isabelle complained of a dry eye problem, which kept making her almost tear up. However, it ended up being beneficial for her portrayal of her character. Canadian actor Daryl Shuttleworth guest stars as a fight promoter in "Warriors". During a readthrough of the script, Shuttleworth decided his character should speak with a British accent like in the film Lock, Stock and Two Smoking Barrels. The producers wanted to cast Rekha Sharma in "Instinct" as she appeared in several other Vancouver-based productions, including Battlestar Galactica. The producers felt she "rocked" her audition, as she brought a lot of energy to her character.