In the show, Louis-Dreyfus stars as Christine Campbell, a somewhat neurotic divorced mother and owner of a women's gym who is in a constant struggle to keep pace with those around her. A frequent fixture in her life is her ex-husband Richard (Clark Gregg) whose new girlfriend (Emily Rutherfurd) is also named Christine, hence the nickname "Old Christine" for the Louis-Dreyfus character. Christine also struggles with her inferiority complex with the snobby 'meanie moms' (Alex Kapp Horner and Tricia O'Kelley) at her son Richie's private school. Hamish Linklater plays Matthew, Christine's live-in brother, and Emmy winner Wanda Sykes portrays Christine's best friend Barb.

The show has featured recurring roles for a wide range of established actors including Blair Underwood, Dave Foley, Scott Bakula, Andy Richter and Jane Lynch.

Season one of The New Adventures of Old Christine consisted of 13 episodes, kicked off by setting up the show's premise. Christine found out at her son's new posh private school that her ex-husband and friend is dating a new, younger girlfriend, also named Christine. Christine then sets out to find some happiness, and begins to date Burton until Christine can't tell him she loves him, leading to a breakup. Christine also had some showdowns with meanie moms Marly and Lindsay, and in the season finale, Christine had a chance to get back with Burton, which was plagued when he found out that she'd kissed with Richard the previous day. New Christine left Richard when he told her, closing the season with a cliffhanger.

Season two had a full 22-episode order, and continued the explosive season 1 finale where Ritchie incorrectly told his new class that Richard and Christine had reconciled. Christine and Richard, following this, unsuccessfully give their relationship another try. The next episode found Christine meet a handsome man and begin to date him, as Richard and New Christine reconciled. However, when Christine, New Christine, Richard and the stranger are in the house, New Christine calls out the man as her father, effectively complicating the once strong relationship. Shortly after in the season, the two broke up.

Still early, Christine and Ritchie's new teacher expressed their feelings for each other but established they couldn't get romantically involved. As the season progressed, Christine sent out an email that found Mr. Harris nearly fired, and Christine realized she had to move on, and she began dating Tom, but the date was ruined when he had diarrhea. Christine and Mr. Harris once again hit it off. As the season began to conclude, Matthew and Barb started to express feelings for each other after a messy wedding where Christine ruined the bride's time and New Christine, again, left Richard. Christine and Richard again slept together where Christine suffered a pregnancy scare, which thankfully was avoided. The season finished with Richard and New Christine together and Christine and Mr. Harris together.

In a 10-episode third season, shortened due to the WGA strike, Christine and Mr. Harris had a smooth going relationship, until Christine's schedule became too hectic midway through the season, and to her dismay, he left her. Christine made a new friend earlier, Mike, who tried to help her through the breakup. Christine then tried dating again but then dated a guy who proved to still be in high school, obviously not going well. Richard and New Christine bought a house and it turned out to be Christine's dream house, not sitting right with her. Matthew and Barb slept together and stayed together to punish Christine, although not into each other in reality. They split up at the end of the season. The finale featured Jason Alexander, as the episode set up a Seinfeld Reunion.

The fourth season, currently airing, debuted on September 24, 2008, and consists of 22 episodes. In the season premiere, Barb discovered that due to her divorce, she would have to be temporarily deported until her paperwork would sort out due to her foreign status. Christine offered to marry her to keep her in the country and Barb reluctantly accepted, even though it was apparent that Christine was much more into the marriage concept than she was. Richard, after many failed attempts, successfully proposed to New Christine. Marly showed up to school a few months pregnant to save her marriage, and moments later a less-pregnant Lindsay comes, who was pressured into pregnancy to revive her friendship with Marly.

Meanwhile, Matthew began his work as a therapist and his first patient "Lucy" played by Michaela Watkins had a problem with a lack of boundaries with authority figures, and this included Matthew. Matthew tried to control himself but the two ended up kissing. They furthered their relationship when they failed to take it slow and slept together, although this strengthened it.

Christine and Barb go on a double date with two random guys, and they both fall in love with their respective dates, and both become part of a couple. Christine realized Patrick was the perfect guy when he accepted Richard as being a part of her life, but she took it too far and he temporarily left her, but the two reconciled