- Shawn Spencer (James Roday) is a freelance consultant with the Santa Barbara Police Department, pretending to be a psychic. However, it is really his exceptional observational skills and eidetic memory that allow him to obtain his "visions." He refuses to take anything seriously, though he has matured slowly throughout the seasons. He has had romantic tension with Juliet since they met, which led them to start dating in the middle of the fifth season, and to get engaged in the 8th season!
- Burton "Gus" Guster (Dulé Hill) is Shawn's best friend since childhood, as well as business partner. He also is a pharmaceuticals salesman. Unlike Shawn, he takes his work very seriously and usually tries to act professionally, yet usually ends up as invested in jokes and snacks as Shawn is. He is famous for his many aliases (usually given to him by Shawn), including "Magic Head," "Lavender Gooms," "Ghee Buttersnaps," and "Control Alt Delete." He is known for being attracted to all types of women, but they are usually crazy or else end up as the prime suspect.
- Carlton "Lassie" Lassiter (Timothy Omundson) is the head detective for the Santa Barbara Police Department. He is skeptical of Shawn's psychic abilities and is extremely annoyed by Shawn's comic antics. However, he occasionally must come to Psych for help with his more difficult cases.
- Juliet "Jules" O'Hara (Maggie Lawson) is a junior detective for the Santa Barbara Police Department and is Lassiter's partner. She joined the SBPD after Lassiter's old partner got transferred in Season 1, and was originally a cop in Miami. Throughout the series, she and Shawn share constant romantic tension, and the two start dating in the fifth season, and get engaged in season 8!
- Chief Karen Vick (Kirsten Nelson) is the SBPD Chief. She is tough but fair, usually reluctant to hire Shawn and Gus for cases, but almost always gives in. She respects Shawn's help and input but firmly keeps him in check (as much as she can) when he pushes the limits of the law and her patience.
- Henry Spencer (Corbin Bernsen) is Shawn's uptight, precise father and a former police sergeant. He is frequently visited by Shawn with questions about various cases but is usually reluctant to help. He was rehired to the SBPD to be in charge of the department's consultants, much to Shawn's chagrin. At the end of Season 6, Henry quit the SBPD after being shot by a former police partner in the season's cliffhanger ending.
- Young Shawn (Seasons 1–5: Liam James, Seasons 5–8: Skyler Gisondo) is the younger version of Shawn Spencer. He is shown at the beginning of most episodes in flashbacks to the late 1980s and early 1990s, usually learning a life lesson from his father, which helps him later in the episode. He has also been portrayed in various episodes by Josh Hayden and Kyle Pejpar.
- Young Gus (Carlos McCullers II) is the younger version of Burton "Gus" Guster. He is shown at the beginning of various episodes in flashbacks with Shawn. He was also portrayed by Isaah Brown during the first season.
- Buzz McNab (Sage Brocklebank) is a naive but lovable cop who often provides Shawn and Gus with clues. He takes every case given him by Lassiter and Juliet with a polite, optimistic attitude, despite both Lassiter and Jules finding the said case to be menial. Shawn gives him a "little boy cat" (that is actually a girl cat) that once helped him solve a case in season one. In "Shawn Gets the Yips", McNab is severely injured when a bomb went off in his mailbox while he was getting his mail. Later in the episode, he returns to work with a severe concussion and on crutches, but alive; he remarks to Shawn and Gus that he had lost part of three toes, though, and when Shawn coughs from dehydration (he thought that his elliptical trainer was rigged with a bomb and a motivational note written by Jules said if his heart rate got below 150 beats/min he would die), he immediately begins to go get Shawn a drink of water before being told numerous times that he should rest. He has occasionally pulled Shawn over for various traffic violations only to realize that it is him and apologize. In the fourth season finale episode, "Mr. Yin Presents...," McNab is attacked and knocked unconscious by the unseen killer, otherwise known as Yin, but survives. He returns in the fifth and sixth seasons.
- Madeleine Spencer (Cybill Shepherd) is a police psychologist who is Shawn's mother and Henry's ex-wife. In the episode "Ghosts" (3.01), she tells Lassiter that she has eidetic tonal memory, which is like Shawn's photographic memory but with sound. She appears in "Ghosts" (3.01), "Murder?... Anyone?... Anyone?... Bueller?" (3.02), "An Evening With Mr. Yang" (3.16), and "Yang 3 in 2D" (5.16). She was portrayed over-the-shoulder by a different actress in "Shawn (and Gus) of the Dead" (2.16).
- Abigail Lytar (Rachael Leigh Cook) is Shawn's high school crush, whom he let get away when he moved from, then back to, Santa Barbara and his parents got divorced. She first appears in "Murder?... Anyone?... Anyone?... Bueller?" (3.02) and returns in "An Evening With Mr. Yang" (3.16), "He Dead" (4.02), "Bollywood Homicide" (4.06), and "You Can't Handle This Episode" (4.10). In "You Can't Handle This Episode", the winter half premiere of Season 4, Abigail departs for Uganda. However, she returns in the episode "Mr. Yin Presents..." (4.16). After being kidnapped by Mr. Yin and saved by Shawn, she tells him she does not like danger and breaks up with him after the two share a final kiss.
- Winnie Guster (Phylicia Rashad) is Gus' mother. She appears in the first two of the series' Christmas episodes, "Gus's Dad May Have Killed an Old Guy" (2.10) and "Christmas Joy" (3.09). She also appears in A Nightmare on State Street in Season 8.
- Bill Guster (Ernie Hudson, Keith David) is Gus' father. Although the character of Gus' father appeared in the first two Christmas episodes, Bill Guster was played by Ernie Hudson in "Gus's Dad May Have Killed an Old Guy" and by Keith David in "Christmas Joy."
- Mr. Yang (Ally Sheedy) is a serial killer, first appearing in "An Evening With Mr. Yang" (3.16). She returns after a decade-long absence to target Shawn in her deadly game of cat-and-mouse. In the Season Four finale, "Mr. Yin Presents..." (4.16), Shawn and Gus visit her in prison. She seems to have a deeper connection to Shawn, as the last scene of "Mr. Yin Presents..." shows Yin, Yang's partner, looking at a picture of what is presumably a younger Yang, standing next to young Shawn. Her help is enlisted again by Shawn and Gus in "Yang 3 in 2D," the fifth season's finale, in which it is revealed that she is actually Yin's daughter.
- Mary Lightly (Jimmi Simpson) was a department psychologist who was an expert on Mr. Yang. He first appeared in "An Evening With Mr. Yang" (3.16) and later in "Mr. Yin Presents..." (4.16). He was stabbed to death in the season 4 finale by Yin while bravely trying to capture him alone. He appears on videotape in "Yang 3 in 2D" (5.16) as well.
- Woodrow Strode (Kurt Fuller) is a police coroner that Shawn shares a mutual respect with. His wife cheats on him with multiple men, some of whom he has approved. He is also apparently wanted in the Philippines. He first appeared in "High Top Fade Out" (4.07).
- Mr. Yin (Christopher Turner, Peter Weller) was a serial killer who was actually responsible for the Yang murders. He is also Yang's father. He first appeared in "Mr. Yin Presents..." (4.16) targeting Shawn, and later returned for a second round in "Yang 3 in 2D" (5.16), in which he is murdered by his daughter.
- Pierre Despereaux (Cary Elwes) is an extremely elusive Canadian art thief. He first appeared in "Extradition: British Columbia" (4.01). When Shawn and Gus travel to Canada on a ski trip they end up catching him. However, it is revealed that he, in fact, is simply an insurance fraudster. Despereaux returned in "Extradition II: The Actual Extradition Part" (5.10), in which he was accused of multiple murders after his escape from prison. He was later cleared of the murder charges and finally extradited to the United States. He makes a return in the episode "Indiana Shawn and the Temple of the Kinda Crappy, Rusty Old Dagger" (6.10), in which he races with Shawn and Gus against a gang of art thieves to find an old dagger. He is also in "Lock, Stock, Some Smoking Barrels and Burton Guster's Goblet of Fire" (8.01), in which it is left up to the viewer whether he is a bona fide Interpol agent or not.
- Declan Rand (Nestor Carbonell) is a rich criminal profiler so good at his job that he poses a threat to Shawn. He turns out to be a fake criminal profiler and knows that Shawn is not a real psychic. His first appearance was in "Shawn 2.0," and his most recent appearance was in "One, Maybe Two, Ways Out." In "Extradition II: The Actual Extradition Part," Juliet announces that she and Declan broke up.
- Marlowe Viccellio (Kristy Swanson) is a woman Carlton Lassiter meets and becomes romantically involved with. It is later discovered that she has been stealing blood in order to help her dying brother, and she is sent to prison. Despite this, her relationship with Lassiter continues. She first appears in "This Episode Sucks" and later in "Let's Doo-Wop It Again." She is released from prison in the season seven episode, "Cirque du Soul." In the next episode, "Deez Nups," she and Lassiter marry.
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