Strickland has cited Jessica Lange, Holly Hunter, Diane Keaton (in Annie Hall), Ione Skye (her Fever Pitch co-star) and Jane Fonda as her inspirations and/or influences; for The Grudge, she mimicked Fonda's performance in Klute (1971) and her "brilliant way in that film of creating tension and fear for the audience just by walking down a hallway and looking over her shoulder." She noted the input of her acting coach, Maggie Flanagan, who instructed Strickland to watch films with the sound turned off to gauge the quality and comprehensibility of a performance, and who Strickland credits as her "Jedi Knight".

Strickland was born in Blackshear, Georgia, to Susan Strickland, a nurse, and Dee Strickland, a high-school football coach, principal, and superintendent. KaDee's birthname is Katherine Dee; her parents combined the K in Katherine with her father's name to make KaDee. She was raised in Patterson, Georgia, which she said is a "one-stoplight town", and she had a job picking tobacco on a local farm for eight years. When she was a child, Strickland watched the Woody Allen film Annie Hall (1975) and was, as she put it, "wanting to be in that place, and being completely taken with the Energy of those people. I wanted to be in it". During her childhood, she was well known locally as a member of the Strickland family and for her extracurricular activities and achievements (she was the Homecoming Queen in elementary, middle, and high school, the student council President, and a cheerleader). She never considered a career in the performing arts until her participation in a one-act play performed by students of her high school: "[...] the minute I set foot on stage, that was it. Destiny took over. There were no other options. I felt like I fit my skin, I knew what I was here to do", Strickland said.

In 1996, Strickland appeared briefly in the music video for Oasis's "Don't Look Back In Anger". In 2009, Strickland appeared in the music video for Rascal Flatts's "Here Comes Goodbye".

Strickland's first lead role came when Producer Doug Belgrad saw the dailies of her scene in Something's Gotta Give. He cast her opposite Johnny Messner and Morris Chestnut in the jungle-set horror film Anacondas: The Hunt for the Blood Orchid, the sequel to Anaconda (1997). Strickland played an accomplished research scientist who travels to Borneo as part of an expedition team searching for a species of plant rumored to have life-extending properties. She said she initially did not want to follow a Woody Allen film with a "snake movie", but that she changed her mind because the hero was a female Southerner who was not "a complete idiot" or "a chick in shorts about to get whacked". Though its box office revenue tripled its production budget, Anacondas did not perform as well as its predecessor, and most reviews panned the project. The cast received positive comment from Variety magazine and the Chicago Sun-Times's Roger Ebert, but a critic for the San Diego Union-Tribune said the film was "so stupidly plotted and badly acted, it becomes unintentionally funny", and described Strickland and her co-stars' work as "garden-variety bad". Other reviews focussed on the attractiveness of Strickland and her castmates; Slant Magazine said "[the film is] populated with anonymous, attractive plastic people from the Los Angeles talent pool." During the same period, The Florida Times-Union referred to her as "the pride of Patterson".

When staying in Philadelphia, Strickland had opportunities to take part in other films in production in and around the city. Those included Rel Dowdell's Train Ride, a date rape thriller filmed in 1998, but not commercially released until 2005 because of financing problems. She was also cast in the crime drama Diamond Men with Robert Forster and Donnie Wahlberg; it opened to sparkling reviews, with Richard Roeper of the Chicago Sun-Times declaring it "a fantastic film, with a good cast". After she moved to New York City, Strickland appeared in Adam Bhala Lough's filmmaking debut, Bomb the System, which received unenthusiastic notices from critics and was not shown outside film festivals until 2005.

Concurrent to her film work, Strickland acquired stage experience in productions such as A Requiem for Things Past in mid-1999, and John Patrick Shanley's Women of Manhattan. She acted in a December 2002 episode of the television show Law & Order: Criminal Intent and made nine guest appearances on All My Children, which enabled her to leave her waitressing job. In 2003, Strickland was cast opposite Eddie Cibrian in the pilot episode for an uncommissioned small screen serial adaptation of John Grisham's novel The Street Lawyer.

Strickland's next project, The Grudge, was another horror film. In Japanese Director Takashi Shimizu's U.S. remake of his film Ju-on: The Grudge (2003), Strickland played (in a role originated by Misaki Ito) a Tokyo-based American businesswoman whose relatives emigrate from the U.S. Strickland received the role through a casting session with Producer Sam Raimi, who picked her based on her work in footage for the then-unreleased Anacondas, and her willingness to work away from home for extended periods. She said that Japan and Japanese cinema had always fascinated her, and that she wanted to be "a part of that world" in which filmmakers communicate the story via action rather than dialogue; she also highlighted the importance of being "able to explore being in the wrong place at the wrong time without being a sex object/damsel in distress." The Grudge was a number-one U.S. box office hit and quickly became one of the year's most profitable films, but reviews were lukewarm. The Charlotte Observer wrote "the cast is drab and lifeless", and earned "nothing but demerits". Strickland's presence in The Grudge and Anacondas led horror fans to name her "[their] newest scream queen", but she said that when deciding what film to do next, she did not focus as much on genre as she did on good characters, scripts, and Directors, which she said "don't come around that often." For the scene in which her character hides under her bed covers, Strickland received a 2005 Teen Choice Award nomination for Choice Movie Scary Scene.

Strickland is an advocate of the arts. In 2004, before the release of Anacondas, she hosted the art debut of fellow Actress Heidi Jayne Netzley at the Edgemar Center for the Arts in Santa Monica, California. Strickland was among the actors who picketed alongside Writers during the 2007–2008 Writers Guild of America strike.

In early 2005, Strickland was cast in the pilot episode for the fact-based ABC television series Laws of Chance. It was based on the career of Kelly Siegler, a highly successful Houston, Texas-based assistant district attorney. Strickland, whose co-stars in the pilot included Frances Fisher and Bruce McGill, said she was "really excited to have the opportunity to portray this phenomenal lady", but the series was dropped from development a few months later. Strickland was also cast in the independently financed 1950s-set film Walker Payne as laid-off stripminer Jason Patric's love interest; in a review of the film at the 2006 Tribeca Film Festival, Variety wrote that Strickland was "elegant". In late 2005, she joined the cast of The Flock, a crime drama featuring Richard Gere, Claire Danes and singer Avril Lavigne about a federal agent assigned to track down a missing girl and a paroled sex offender (played by Strickland). Strickland said it was important to participate in such a story because she felt members of society need to consider and be responsible for their views on the sex offender counterculture, which she says "[is] actually not counter at all, it's very real, very next door to you."

Strickland met Jason Behr, her co-star in The Grudge, on the set of the film in 2004. According to her, they had a shared affinity for Japan and Japanese culture and became best friends almost instantly because of their mutual willingness to explore it. The two began a relationship soon after filming ended. When asked about her love life in February 2005, Strickland said it was "quiet". On November 10, 2006, she married Behr in Ojai, California, in a ceremony that included elements of Japanese culture. Strickland said her experience planning the wedding aided her preparation for her role in The Wedding Bells. Her work on the wedding provided the inspiration for the wedding garden of Casa de Estrellas (House of Stars), a Santa Fe, New Mexico, luxury inn and spa. Behr proposed to her on her birthday. On October 17, 2013, the couple welcomed their first child, a son named Atticus Elijah Behr.

Strickland's first aired television project as a cast regular was the David E. Kelley-produced series The Wedding Bells. According to her, she wanted to be in the series because "the subject of love and commitment is something to me that I want to walk into every day. It's a lot better than dead bodies." The show began airing on the Fox Network in March 2007, and it was canceled the following month. The Baltimore Sun called it "awful in ways that make the word 'awful' seem inadequate [...] [the cast is] not a bad one at all, but just terrifically ill-served by the material." She joined the cast of the Grey's Anatomy spin-off Private Practice, which began airing in September 2007; and portrayed Charlotte King, chief of staff at the show's local hospital and a Doctor specializing in urologic surgery, and later sexology.

Strickland is a self-described "big fashionista" and "very concerned with looks", and she has noted the need for "an element of vanity" in acting, particularly in Los Angeles, where she says she is "continually surrounded by super-human people [...] I've never seen so much beauty." According to her, she has never had to rely on her appearance or felt pressurised to be beautiful—"The truth is I'm not that girl", she said. With regard to sources such as magazines, Strickland said she is "very careful" about the way she wants to be presented as a woman, saying she strives to avoid "sensationalizing or sexualizing" herself. As she put it, she is not accustomed to being considered a "pretty girl" or "attractive by a standard that I've never felt that I was part of". Strickland has a very audible Southern American accent, which she says is an advantage for her because it is "the one thing" that film and casting Directors like the sound of and "really gravitate toward", particularly in Los Angeles, which she called "a town full of blondes". According to her, she learned to speak without the accent at university, and because she does not want people to think she has no other skills, she uses it only when it is required or requested. Strickland is experienced in stage combat and said she "like[s] to do physical stuff"; in an interview to discuss Anacondas, she said "if there was a Braveheart for women, I'd be all over it."