In the fall of that year, Scolari and Hanks premiered in "Bosom Buddies", playing two low-level advertising agency workers who disguise themselves as women in order to live in an all-female residential hotel. The show was never highly rated, and ABC pulled it after a season and a half, but the chemistry between Scolari and Hanks was applauded and the viewers who found the show were intensely loyal. ABC gave Scolari his own comedy for the 1983 season, "Baby Makes Five", in which he was an accountant and young husband, but that show also did not click.
In 1984, Scolari joined the cast of "Newhart" and until the end of the series' run in 1990, was one of the most popular members of its ensemble, marrying Julia Duffy on the show and forming an hilarious "me generation" couple. When "Newhart" was canceled, there was talk of a spin-off for Scolari and Duffy, but, instead, Scolari went on to star in the short-lived "Family Album". This 1993 CBS series cast him as an architect who returns to Philadelphia with his family. Also short-lived was the 1995 effort "Dweebs", another ensemble show set in a computer software company with Scolari as the trampoline-jumping head of development. The actor followed up with the successful TV series adaptation of the Disney hit film franchise "Honey, I Shrunk the Kids" (1997-2000), taking over the Wayne Szalinski role from the films' Rick Moranis.
In between series, Scolari appeared in some TV-movies, beginning with "Missing Children: A Mother's Story" (CBS, 1982). In 1983, he did the frothy ensemble comedy "Carpool" (CBS). Scolari also provided voices for animation, particularly for the syndicated series "Gargoyles". His other TV work included the 1996 Arts & Entertainment Channel production of the Anthony Newly-Leslie Bricusse musical "Stop the World, I Want to Get Off".
Scolari's feature film work has been sporadic. He played a buffoonish owner of a resort in "Rosebud Beach Hotel" (1984), and co-starred with Mary Crosby in "Corporate Affairs" (1990), a romantic comedy in which Scolari takes advantage of Crosby when he thinks his boss is deceased. In 1994, he had a supporting role in "Camp Nowhere", a mildly funny summer amusement.
Scolari's old friend Hanks, making his feature screenwriting and directing debut, cast his former co-star in a small role as a TV variety show host in "That Thing You Do!" (1996), about a successful 60s-era rock band. They would reunite again when Scolari played astronaut Pete Conrad in "From the Earth to the Moon" (1998), the Hanks-produced, highly acclaimed HBO miniseries chronicling the advent of the U.S. space program. The two actors next collaborated on "The Polar Express" (2004), in which Scolari suited up in a Performance Capture suit to provide the template for the CGI-created character Lonely Boy.