In June 1998, she married Eric Nederlander, a theatrical Producer and the son of theater owner Robert Nederlander. Several months before the wedding, she met Jerry Seinfeld at a Reebok Sports Club. After returning from an Italian honeymoon with Nederlander, she took up with Seinfeld; Nederlander filed for divorce in October 1998, only four months after marrying. Sklar and Seinfeld became engaged in November 1999, and were married on December 25, 1999. Comedian George Wallace was the best man at the wedding.

The Seinfelds have three children. Daughter Sascha was born on November 7, 2000, in New York City, son Julian Kal on March 1, 2003, in New York City, and Shepherd Kellen was born on August 22, 2005, at NewYork–Presbyterian Hospital.

Seinfeld founded Baby Buggy in 2001 following the birth of her first child. She started with a donation drive, whereby she asked people for their used baby supplies after realizing that her first child's products, no longer of use to her own family, could certainly be used by others. According to Seinfeld, "shortly after the birth of my daughter, Sascha, having slowly accumulated closets full of used—but very usable—baby clothing and equipment I no longer needed, I had a moral dilemma. As the daughter of a social worker, throwing out perfectly good baby gear was unthinkable, and yet there was no easy way to get it to a family who could use it. Thus, Baby Buggy was born."

After much criticism from Nederlander on Sklar's divorce and subsequent marriage, the Seinfelds gave a personal account of their relationship to Vogue Magazine in 2004. Jessica Seinfeld is quoted as saying,

In the same lawsuit, Lapine also accused Jerry Seinfeld of defamation, after he appeared on Late Show with David Letterman on October 29, 2007 and called Lapine "angry and hysterical," a “wacko,” a “stalker” and a “nut job,” and suggested that "people with three names ... become assassins."

Seinfeld's first book Deceptively Delicious was published by HarperCollins on January 7, 2008, and contained a series of recipes to hide pureed fruits and vegetables inside children's meals. Following her book's release, another cookbook author, Missy Chase Lapine, sued both Seinfelds, accusing Jessica of copyright and trademark infringement. Lapine had unsuccessfully shopped her own manuscript, The Sneaky Chef, to several publishers, including HarperCollins, before publishing with Running Press. In response to the accusations, Seinfeld denied that either author had invented the idea of hiding fruits and vegetables in children's meals, and asserted that "countless prior works utilized this very same unprotectable idea" in cookbooks dating back to 1971. She claimed, "My book came from years of trying to get my own children to eat healthy foods—my own trial and error in my own kitchen. The idea of pureeing vegetables has been around for decades."

On September 10, 2009, United States District Court for the Southern District of New York Judge Laura Taylor Swain dismissed all claims against Jessica Seinfeld, but left open the claim of defamation against her husband, to be tried in the New York state Supreme Court located in Manhattan. The federal judge ruled that "no reasonable fact finder could conclude" that any copying occurred, and that the books were "very different" and had "a completely different feel." Lapine appealed the decision, but it was also dismissed by the United States Court of Appeals for the Second Circuit on April 28, 2010. In February 2011, the state court dismissed the remaining defamation claim against Jerry Seinfeld.

In October 2010, Jessica launched a website for beginner cooks called "Do it Delicious." The website teaches at-home viewers how to prepare particular dishes or meals step-by-step, as well as a kitchen guide, store, blog, and community forum where users can submit tips and ask how-to questions.

In 2013 she released her third cookbook, The Can't Cook Book, billed as "100 recipes for the absolutely terrified!" In 2017 she released her fourth cookbook, Food Swings.

Baby Buggy works with a network of over 50 community-based organizations (CBOs) that are carefully selected—each applies annually to become a recipient. Some of the organizations that have partnered with Baby Buggy include organizations working with victims of domestic violence such as Safe Horizon and New York Asian Women’s Center; multi-service sites including Single Stop East Harlem and Lenox Hill Neighborhood House; prenatal and NICU units at hospitals such as Woodhull and NY Presbyterian; immigrant and refugee-serving organizations including the International Rescue Committee; and parenting programs, such as the Nurse-Family Partnership program and the Harlem Children’s Zone’s Baby College.

In 2016, Baby Buggy was rebranded as the Good Plus Foundation (also seen as Good+ Foundation). As Baby Buggy, the nonprofit had seen 20 million items donated to families across the United States. Jessica shared with "Good Morning America" co-anchor George Stephanopoulos that the charity had outgrown its name. The Good Plus Foundation pairs goods and services in an incentives program. For Example, a parent who opens an education savings account will also receive a stroller.

Jerry Seinfeld has said, "If it wasn’t for Jess and the kids, I’d really blow my brains out. Jessica saved my life. She gave me something to care about."