After recording songs with the aforementioned producers, Milian took a break from music and started filming Bring It On: Fight to the Finish. When Milian returned to music, she concentrated on promoting her single "Us Against the World", and shot its music video. Since then, Milian said that she became "a little bit more meticulous with what I feel deserved to be on the album", and resumed recording. Songs recorded for the album included the 1990s Madonna-styled ballad "Stay", Euro-club record "Tug of War" and the feel-good song "Diamonds", which featured Kanye West. Other features included Rick Ross on the Cool & Dre produced track "Blissful", and Pitbull.

Milian starred in Be Cool, the sequel to Get Shorty, with John Travolta and Uma Thurman, and recorded two songs for its Soundtrack. She was then cast in a lead role in the horror film Pulse, starring alongside Kristen Bell and Ian Somerhalder. The film was a remake of the Japanese film Kairo (2001), and was adapted by Wes Craven and Ray Wright. Filming took place in Romania, a traumatic time for Milian, where she endured racial abuse and discovered that boyfriend Nick Cannon was cheating on her. Milian has also appeared in two video games: Def Jam Vendetta (2003), where she plays Angel, a mob boss' girlfriend, and as one of the female leads, Carmen Mendez, in the video game Need for Speed: Undercover (2008).

Milian's first major acting role was offered by the Disney Channel to join The Mickey Mouse Club; however, she did not accept and opted to star as a reporter on Movie Surfers. During this time, she had minor roles in film and television, including Sister, Sister, Smart Guy, The Steve Harvey Show, Get Real, The Wood and American Pie. In 2002, Milian was appointed the host of the live competitive music series Becoming Presents: Wannabe on MTV, where she met Director Joseph Kahn. Kahn suggested she audition for a lead role in the film Torque. Her audition was successful and she played a minor role in the film. She was subsequently cast in her first lead role in Love Don't Cost a Thing. Milian has been described as a role model to young girls; she has said that there are a lot of people who young girls look up to, but "at the end of the day you have to be your own person and love yourself." Milian worked with the Children Uniting Nations charity, in which she was a big sister to foster children, and says her favorite charity is the Penny Lane Foundation. Milian was awarded with a humanitarian award at The Reign fundraiser from the Elton John AIDS Foundation for being a role model for young children. Milian said, "I've never been rewarded that way and never been acknowledged like that. That was really nice of them, and I was happy I was able to show up for the kids."

Milian felt that Island Def Jam was confused as to how they wanted her image to be portrayed; one second she was young and singing "AM to PM", and next she was a grown woman singing "Get Away". She realized that the change confused the audience, and that "nobody was buying it". In 2003, Milian's label Def Soul was shut down and absorbed by its parent Def Jam, although Milian was instead moved over to Island Records. After the international release of her debut album, Milian went back into the recording studio. The singer felt that music trends had changed into rock music, hardcore hip hop and tribute songs, and her music did not fall into those categories. Milian decided to stop recording and toured overseas for a year and a half. When she returned to the US, she decided not to release her previous album domestically, and started working on a new album. Milian traveled the world, working with the popular producers Bloodshy & Avant, "Darkchild", Cory Rooney, Warryn Campbell, Bryan-Michael Cox and Polli Paul.

Milian's second studio album, It's About Time, was released in the US on July 13, 2004. The critical response to the album was mixed; the club tracks, most notably lead single "Dip It Low", were praised while the ballads were said to be disappointing. The style and sound of the album was compared to that of Beyoncé and Jennifer Lopez by several critics. Milian later admitted that her new sexy image for "Dip It Low" and the whole album was mainly for shock value. She had to make her way back into the US market, and by choosing a sexier image, she made a name for herself. "Dip It Low" was also meant to show that she was not the same 18-year-old girl in the "AM to PM" video. To create her new image, Milian also decided to change her appearance and lightened her hair. Taking inspiration from Janet Jackson who constantly changed her image, Milian thought to herself, "'When did I like Janet Jackson the most?' It was when she had her lightened hair."

Milian believed that the album was more R&B when compared to her "bubble-gum" pop debut album. The change was reflected in the album's lead single, "Dip It Low", which was more of a club and R&B track than her previous pop release "AM to PM". Milian performed as an opening act on the Usher and Kanye West tour to promote her album. The album debuted and peaked at number 14 on the Billboard 200 album chart and number 21 in the UK, selling a total of 382,000 and 63,708 copies respectively, and received a Grammy Award nomination for "Best Contemporary R&B Album" in 2005. The album's first single, "Dip It Low", became Milian's biggest hit to date, reaching number two in the UK and number five in the US. The single was certified Gold by the RIAA for digital sales, and earned a Grammy Award nomination for "Best Rap/Sung Collaboration". The album's second and final single, "Whatever U Want", featuring Joe Budden, failed to reprise the success of the lead single but reached the top ten in the UK.

After the production of So Amazin' in 2006, Milian began dating Andre Lyon from the production group Cool & Dre. The pair dated until February 2009, when they decided to go on a break. Milian said that they were still really close, and decided to break up because it was "hard to grow together when you live on two different coasts". The singer wanted to take more opportunities and learn more about herself, which she often let go when in a relationship, but felt that she was in a now-or-never situation. Milian described Lyon as an amazing guy, and said that although there was a chance for the couple in the Future, she needed to focus on herself.

Milian met actor Nick Cannon on the set of their film, Love Don't Cost a Thing, in 2003, and they began dating. After being together for two and a half years, Milian ended her relationship with Cannon in 2005 because of his cheating. Cannon revealed that he refused to stay faithful to Milian because their relationship was becoming too much like a "Christian romance". When Cannon married Mariah Carey on April 30, 2008, Milian said, "regardless of what I felt in the past at the time, I actually forgive him and I'm very much over that."

In February 2009, reports emerged that Milian was dating musician The-Dream. Music Producer Dre of Cool & Dre said that he supported Milian's relationship with The-Dream, "I think it's gonna be a good fit for her". He stated that he had "nothing but love for her and her family", and that he "wish[ed] her the best and we're definitely looking forward to what she's got going on". In late May 2009, it was reported that Milian and The-Dream were getting married, and the couple celebrated their engagement party in Las Vegas in June. On September 4, 2009, Milian and The-Dream eloped at the Little White Chapel in Las Vegas, Nevada. MTV reported that Milian and The-Dream would get married again in Rome, Italy, and then renew their vows in the US in front of family and friends. On September 11, 2009, it was announced that Milian and The-Dream were expecting their first child together. The Daily Mail reported that "the pregnancy was a surprise, but they were getting married regardless". On February 26, 2010, Milian gave birth to their daughter Violet Madison Nash, who had "a full head of hair." Violet was Milian's first child, and the fourth for The-Dream, who had three children with ex-wife Nivea. Christina Milian keeps Violet in touch with her Latina roots practicing Spanish with her and cooking Cuban food:

In February 2010, it was announced that Milian had signed an Australian music duo, Kasey Osborne and Kelsey-Maree Eckstein, as their manager. Milian said, "the girls have everything it takes to be the biggest international pop duo out there. The world is definitely ready for these beautiful girls to hit the stage and kill it on screen." She said that the duo were the "most exciting project" she had worked on, and were writing and recording an album to be released in 2010. In September 2010, Osborne stated that she was working on a solo album with Milian, was scheduled to release in 2011, but never did. The album project was pushed back to an unknown release date. Eckstein remained acting and working on her solo music, which was released late 2011. In early 2012, Eckstein released her Official Music Video to "The Revolution", which was written by The Movement and Jesse McCartney and produced by The Movement. In September 2012, Eckstein signed with Brillstein Entertainment Partners as her acting management.

In July 2010, The-Dream announced that he and Milian had separated in late 2009, only three months after their wedding in September of that year. Their divorce was finalized on October 23, 2011.

In October 2012 during an interview, Milian spoke of her Young Money debut: "Wayne just gets his artists, which is great, I have a very one-on-one Business relationship with everybody from Mack Maine to Wayne. They're just very involved in the project as far as bringing the music, playing songs, just giving their input. [...] I really want to pick the perfect single though. It's been a second since I've been out musically, so I do not want to fail and I don't believe in failure, so I just try new things and figure out the pieces. That's one thing that's great about Wayne. He's like, 'Work with different producers, take your time, but at the same time, try new things. Don't be stuck on one thing.'" In July 2013, it was discovered that her contract with The Voice would be ended.

In September 2010, Christina began dating Jas Prince, son of Rap-A-lot Records CEO, James Prince. On September 2, 2013, It was confirmed that Christina and Jas have been engaged since before April. Christina moved out of the couple's home on June 19, 2014, and the couple announced the following day that their engagement had been called off.

In July 2014, it was rumored she was dating Rapper Lil Wayne, with whom she attended the ESPY Awards. They later confirmed their relationship in mid-2015 after which they received criticism from their interconnected exes, singer Nivea and Songwriter The-Dream. They split at the end of 2015 after collaborating on various singles, videos, and concert dates.

Her EP "4U" was released on December 4, 2015 which includes four tracks and music videos packaged in one.

In 2016, she collaborated with So Solid Crew's MC Harvey on the dance track "We Own the Night" which premiered on August 12, 2016.

In June 2017, she appeared as a judge/panelist on the Fox television show, Superhuman. Superhuman features contestants who possess a distinct, nearly super-human ability in fields such as memory, hearing, taste, touch, smell, sight and more are challenged to push their extraordinary skills to win a $50,000 grand prize.