• Bill Murray as Bob Wiley
• Richard Dreyfuss as Dr. Leo Marvin
• Julie Hagerty as Fay Marvin, Leo's wife
• Charlie Korsmo as Sigmund "Siggy" Marvin, Leo & Fay's son
• Kathryn Erbe as Anna Marvin, Leo & Fay's daughter
• Fran Brill as Lily Marvin, Leo's sister
• Tom Aldredge as Mr. Guttman
• Susan Willis as Mrs. Guttman
• Roger Bowen as Phil
• Doris Belack as Dr. Catherine Tomsky
• Marcella Lowery as Betty
• Reg E. Cathey as Howie
• Joan Lunden as Herself

Before Frank Oz was hired to direct, Garry Marshall was considered, and Woody Allen was approached to play Dr. Marvin. Allen was also considered to direct and possibly co-write the script with Tom Schulman. However, because Allen had always generated his own projects rather than getting handed an existing property to make his own, Oz was hired to direct. Allen also declined the role of Dr. Marvin, thus Richard Dreyfuss was ultimately cast. Patrick Stewart was also considered for the role. Early in development, Robin Williams was attached to the project.
What About Bob? was filmed in and around the town of Moneta, Virginia, located on Smith Mountain Lake. For the scene in which Bob accidentally blows the house up, producers used a ⁠3/4⁠-sized model replica of the actual house that they detonated on a nearby lot. The scenes of Bob arriving in town on the bus with his goldfish were filmed in downtown Moneta, which was repainted for the movie. The local institute where Leo tries to commit Bob is actually the local Elks National Home for retirees in the nearby town of Bedford, Virginia. Scenes were also shot in New York City. According to Oz, Murray was "really frightened" about filming in the city. Murray said that he improvised a lot in the film.
Oz has confirmed in interviews that there was conflict on the set during the making of the film. In addition, both Murray and Dreyfuss have stated in separate interviews that they did not get along with each other during filming:

It's entertaining—everybody knows somebody like that Bob guy. [Richard Dreyfuss and I] didn't get along on the movie particularly, but it worked for the movie. I mean, I drove him nuts, and he encouraged me to drive him nuts. — Bill Murray, March 19, 1993 interview with Entertainment Weekly

How about it? Funny movie. Terribly unpleasant experience. We didn't get along, me and Bill Murray. But I've got to give it to him: I don't like him, but he makes me laugh even now. I'm also jealous that he's a better golfer than I am. It's a funny movie. No one ever comes up to you and says, "I identify with the patient". They always say, "I have patients like that. I identify with your character". No one ever says that they're willing to identify with the other character. — Richard Dreyfuss, October 8, 2009 interview with The A.V. Club

Oz himself also verified that there was a feud between Murray and Dreyfuss:

I was just trying to get the best out of both of them. Richard is a very structured person. And I'm not that structured. And Billy is very unstructured. So you have that opposite going also. And as a matter of fact, I just wrote Richard a letter, after all these years, because I was looking at that movie, and I realized how brilliant Richard's work was. But yes, they didn't get along. And in my perverse directorial intent, I was very pleased [laughs]. They're not supposed to get along. It's not that I was simpatico with Bill, but I leaned more towards the ideas that Bill had. But I am so grateful to Richard for his performance. — Frank Oz, January 28, 2021 interview with Rolling Stone

In subsequent interviews, Dreyfuss reiterated what he said of his experience working with Murray, notably when he appeared at Fan Expo Canada in 2017. Dreyfuss further alleged in 2019 that at one point during the production, Murray screamed at him while intoxicated, telling him "Everyone hates you! You are t…

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What About Bob? was released in the United States and Canada on May 17, 1991. During its opening weekend it grossed a total of $9.2 million from 1,463 theaters—an average of $6,299 per theater—making it the highest grossing film of the weekend, ahead of F/X2 ($3.9 million) and Madonna: Truth or Dare ($3.4 million), both in their second weekend. In its second weekend—taking place over the extended 4-day Memorial Day holiday—What About Bob? fell to the number 2 position with an $11.2 million gross, placing it behind Backdraft ($15.7 million) and ahead of Hudson Hawk ($7.1 million), both films making their debut. What About Bob? fell to the number 3 position in its third weekend with a $6.4 million gross, behind the debut of Soapdish ($6.7 million) and ahead of Thelma & Louise ($4.2 million), in its second weekend.

What About Bob? remained in the top-ten highest-grossing films for seven weeks. In total, What About Bob? grossed $63.7 million compared to its $39 million budget, making it the 15th highest-grossing film of 1991. This also made it Buena Vista's second highest-grossing live action film of the year behind Father of the Bride.
Review aggregation website Rotten Tomatoes gives What About Bob? an 82% approval rating based on reviews from 44 critics and an average rating of 6.50/10. The site's consensus reads: "Bill Murray and Richard Dreyfuss' chemistry helps make the most of a familiar yet durable premise, elevating What About Bob? into the upper ranks of '90s comedies".

When the television program Siskel and Ebert reviewed the film, Roger Ebert gave the film a "thumbs up" rating praising the different performances of Bill Murray and Richard Dreyfuss onscreen together as well as most of the film's humor. He said it was Bill Murray's best film since Ghostbusters in 1984. Gene Siskel gave it a "thumbs down" rating and felt Murray gave a very funny and enjoyable performance in the film, but was rather upset by the Dreyfuss character and his angry and arrogant behaviors. He felt it would have been funnier if Dreyfuss had not given such an angry performance in the film and said that Dreyfuss ultimately ruined the film for him. Leonard Maltin said it is "a very funny outing with Murray and Dreyfuss approaching the relationship of the road runner and the coyote". Maltin faulted the film only for its ending, which he found very abrupt and silly. Lou Cedrone from The Baltimore Sun criticized the film: "It is too predictable and deals with a situation that is more irritating than amusing".

Bravo ranked it number 44 on their 2013 list of the "100 Funniest Movies", behind Shampoo and Pee-wee's Big Adventure.