After returning to America in 1984, he was hired as chef de cuisine at La Reserve in New York, before leaving to open Rakel in early 1987. Rakel's refined French cuisine catered to the expensive tastes of Wall Street executives and received a two-star review from The New York Times. Its popularity waned as the stock market bottomed out and at the end of the 1980s, Keller left, unwilling to compromise his style of cooking to simple bistro fare.

Prior to the opening of The French Laundry, Thomas Keller started a small olive oil company called EVO, Inc. in 1992, with his girlfriend of the time, to distribute Provençal-style olive oil and red wine vinegar. Recently, Keller started marketing a line of signature white Limoges porcelain dinnerware by Raynaud called Hommage Point (in homage to French chef and restaurateur, Fernand Point) that he helped design and a collection of silver hollow ware by Christofle. He has also attached his name to a set of signature knives manufactured by MAC.

In 1999, Thomas Keller published The French Laundry Cookbook, which he considers his definitive book on cuisine. That year it won three International Association of Culinary Professionals (IACP) awards for Cookbook of the Year, Julia Child "First Cookbook" Award, and Design Award. In 2004 he published "The Bouchon Cookbook," although he gives most of the credit to Bouchon chef Jeffrey Cerciello. Other cookbooks that he has written or contributed are The Food Lover's Companion to the Napa Valley, Under Pressure: Cooking Sous Vide, Ad Hoc at Home (2009) and Bouchon Bakery (2012). He provided an introduction or foreword to The Vineyard Kitchen: Menus Inspired by the Seasons by Maria Helm Sinskey, "Happy in the Kitchen" by Michel Richard, "Indulge: 100 Perfect Desserts" by Claire Clark (head pastry chef at The French Laundry), the new publication of "Ma Gastronomie" by Fernand Point, "Charcuterie: The Craft of Salting, Smoking, and Curing" by Micheal Ruhlman and Brian Polcyn. He is also featured in "My Last Supper" by Melanie Dunea

After the success of The French Laundry, Thomas and his brother, Joseph Keller (currently owner/chef of Josef's in Las Vegas), opened Bouchon in 1998. Located down the street from The French Laundry, it serves moderately priced French bistro fare, with Bouchon Bakery opening next door a few years later (in 2006 Keller opened a branch of the bakery in the Time Warner Center in Manhattan). Keller has joked in the past that the motivation for Bouchon's opening was to give him somewhere to eat after work at The French Laundry. On January 26, 2004, Keller opened his restaurant Bouchon in Las Vegas. On February 16, 2004, Keller's much anticipated Per Se restaurant opened in the Time Warner Center complex in New York under the helm of Keller's Chef de Cuisine, Jonathan Benno. Per Se, which was designed from scratch and custom-built as part of the overall construction process, was an immediate hit on the New York restaurant scene, with reservations booked months in advance and publications including The New Yorker and The New York Times giving rave reviews. The latest restaurant, "ad hoc", opened in September 2006 in Yountville with a different fixed price comfort food dinner served family style every night. Originally intended to be a temporary project while Keller planned his lifelong dream restaurant for the location, serving hamburgers and wine, he decided to make ad hoc permanent and find a new location for the hamburger restaurant due to its overwhelming popularity.

In 2005, he was awarded the three star rating in the inaugural Michelin Guide for New York City for his restaurant Per Se, and in 2006, he was awarded three stars in the inaugural Michelin Guide to the San Francisco Bay Area for The French Laundry. He is the only American chef to have been awarded simultaneous three star Michelin ratings for two different restaurants. He currently holds seven Michelin stars total: three at Per Se, three at The French Laundry, and one at Bouchon.

Working on the film Spanglish, Keller designed and taught star Adam Sandler to cook what is often called "the world's greatest sandwich", as a plausible Example of what a talented bachelor gourmet might cook for himself. The sandwich resembles a typical BLT, with the addition of a fried egg. In an interview with Vogue Man Arabia he described the BLT as "the perfect sandwich". Keller served as a consultant for the 2007 Pixar animated film Ratatouille, allowing the Producer to intern in the French Laundry kitchen and designing a fancy layered version of ratatouille, "confit byaldi", for the characters to cook. In the American version he plays a cameo appearance as a restaurant patron (the part is played by one of Keller's mentors Guy Savoy in the French version, and Ferran Adrià in the Spanish one).

Keller is the President of the Bocuse d'Or U.S. team and was responsible for recruiting and training the 2009 candidates. The former French Laundry Chef de Cuisine Timothy Hollingsworth won the Bocuse d'Or USA semi-finals in 2008, and represented the U.S. in the world finals in January 2009 under Keller's supervision where he placed 6th, equaling the best performance of the U.S. in the contest to date. On describing his reasons for accepting the Bocuse d'Or Team USA presidency, Keller stated, "When Chef [Paul] Bocuse calls you on the phone and says he’d like you to be President of the American team, you say, ‘Oui, chef’. He’s the role model, the icon".

In 2012 he announced he was at the point of his career when it was time to step away from the kitchen. The important thing, he said, is to make sure to give to young chefs the right things, the right mentoring because "if we're not truly working to raise the standards of our profession, then we're not really doing our job".