In December 1984, Bronson Pinchot garnered notice for his role in Beverly Hills Cop as Serge, an effeminate art-gallery employee with an unplaceable foreign accent. When Miller and company pitched Pinchot as the star of their immigrant show, ABC signed on to the project, originally entitled The Greenhorn. By this time, however, Pinchot had become unavailable, as he had taken the role of a gay attorney in the NBC series Sara alongside star Geena Davis.

Sara failed to find an audience, and was canceled by May 1985. With Pinchot now available, Miller and Boyett began to develop the show in earnest. By November, Comedian Louie Anderson was cast as the immigrant's American cousin. A pilot episode was put into production, but in the end Anderson was not considered right for the role.

Airing in the coveted timeslot between Who's The Boss? and Moonlighting, Perfect Strangers was an instant ratings hit in the spring of 1986, landing in the season's top 10 highest-rated shows.

For season three, the opening sequence was overhauled. The sequence begins with a close-up on Larry and Balki on the back of a tour boat heading east down the Chicago River, then zooming out to show them traveling under the Irv Kupcinet Bridge (the Wrigley Building and the now-demolished Sun-Times building can be seen in the background). A much larger version of the second season series title is superimposed on this image. During the third season only, light Sparkles across this title. The sequence briefly recaps Larry and Balki's journeys to Chicago using footage from the earlier seasons. When Larry passes under the "Welcome to Chicago" sign this time, the sequence cuts to new footage of Larry and Balki around Chicago, including jogging in Lincoln Park, braving a wind gust on a city street, attending a Chicago Cubs game at Wrigley Field, and messing around in a revolving door. After a view of an El train moving over the city street, the sequence concludes with Larry and Balki emerging from the subway to attend the Chicago Theatre. The theater marquee shows, appropriately enough, Neil Simon's The Odd Couple. The new location shots were filmed on September 11 and 12, 1987. This sequence remained the same from season three through the end of the series in season eight.

Perfect Strangers was produced by Miller-Boyett Productions in association with Lorimar-Telepictures, which later became Lorimar Television in 1988. The show, for its entire run, was executive produced by Thomas L. Miller and Robert L. Boyett, and series creator Dale McRaven was executive Producer with them for the first two seasons, becoming an executive consultant thereafter. william Bickley and Michael Warren, who became longtime associates of Miller and Boyett, were supervising producers during seasons one through four, elevating to co-executive producers in season five and finally executive producers with Miller and Boyett from seasons six through eight. Chip and Doug Keyes, who also served as producers on Miller and Boyett's first project under Lorimar, Valerie (later The Hogan Family), were producers on Perfect Strangers during its first season. Others who joined or remained on the production staff for several seasons included Paula A. Roth (who eventually became a principal showrunner in the seventh season alongside the senior executive producers), Alan Plotkin, Terry Hart, James O'Keefe, and the team of Barry O'Brien & Cheryl Alu.

Perfect Strangers had a spin-off series, the highly rated, long-running family sitcom Family Matters, which aired from September 22, 1989, to July 17, 1998. The series was centered around Harriette Winslow (Jo Marie Payton) in the role she originated on Perfect Strangers (Harriette was played by Judyann Elder for the second half of season nine after Payton's departure), and her cop husband Carl (Reginald VelJohnson; the character was initially introduced on Perfect Strangers in the fourth-season episode "Crimebusters") and their family. The series, which initially garnered modest ratings for most of its first season, became a ratings hit after the Winslows' annoying, accident-prone, budding Inventor next-door neighbor Steve Urkel (Jaleel White), was introduced midway through the show's first season.

By the fall of 1991, ABC had been reaping the rewards of the successful TGIF and wanted to capitalize on the preteen-and-younger demographic for the lineup. An industry insider reported that ABC was looking for a reason to cancel Perfect Strangers, because it was becoming too costly to produce and was considered an aging program that did not fit into the new TGIF target demographic.

In late January 1992, the network rolled out plans to launch a similar family-friendly comedy block for Saturday, also helmed by TGIF creator Jim Janicek. It was announced that Perfect Strangers would move from TGIF to join this new lineup to help it take off. On February 1, 1992, Perfect Strangers began airing in the 9 p.m. slot of I Love Saturday Night, the new TGIF sister lineup (which included Growing Pains, Who's the Boss?, and Capitol Critters). The series experienced a drastic decline in ratings. It dropped to #65 for the remainder of the season. In July 1992, ABC moved Perfect Strangers back to Fridays at 9:30 p.m. ET to fill the timeslot with reruns until the new TGIF season began. The reruns that were aired won their timeslot as they had before.

In its six-episode final season, which was filmed during August and September 1992 but broadcast from July 9 to August 6, 1993, it was rated in the top 20 with its series finale attracting 15 million households and rated #11 for the week of August 1, 1993. The average Nielsen ratings for the entire run of eight seasons was #27. For the abbreviated eighth season, Perfect Strangers once again aired Fridays at 9:30/8:30c.

The series aired on Nick at Nite, first with a 6-episode marathon on July 14, 2000, and then a special airing in November 2000; the series aired regularly in late nights from February 3 to September 20, 2003. TV Land aired reruns from August 2, 2002 to September 28, 2002 and January 3 to February 1, 2003, as part of its now-defunct "TV Land Kitschen" weekend late night block, though special episodes aired on the channel in December 2000, April and December 2001, December 2002, January and December 2003, and June 2005. From October 1 to November 1, 2007, ION Television aired reruns of Perfect Strangers on its primetime lineup Monday-Thursday nights at 8:30 p.m. (ET/PT). It is not currently broadcast on either broadcast or cable television in the U.S..

The season four episode "Maid to Order" was released as part of a limited edition bonus disc of the complete first season DVD of Night Court on February 8, 2005 by Warner Home Video.

Various episodes were seen on AOL's In2TV video-on-demand Service starting in March 2006, though after AOL's June 2009 announcement of its split with Time Warner, the series was moved to the AOL Video site.

In February 2008, Warner Home Video released seasons 1 and 2 of Perfect Strangers on DVD in Regions 1, 2 & 4. Further planned season releases ultimately did not materialize. In an article on TVShowsOnDVD.com regarding TV series with stalled DVD releases, it was mentioned that the main hold-up for any subsequent releases of Perfect Strangers is not poor sales but rather high music licensing costs. It is noted that the series sometimes featured popular songs within certain episodes, though the versions by the artists who originally performed them were usually not used; instead they were commonly sung a cappella by Mark Linn-Baker and/or Bronson Pinchot's characters whenever the script called for Balki and/or Larry to sing within the episode.

Outside of the United States, the series aired in the Netherlands by public TV, in Turkey by the Turkish Radio and Television Corporation dubbed in Turkish. In Pakistan, reruns were carried by Pakistan Television Corporation in its original form. In Bangladesh, reruns were carried by BTV in its original form. The series aired in the United Kingdom (on BBC1), Australia and New Zealand (on Channel 2, now called TV2) in its original form; reruns aired in Australia on 7TWO between March and October 2011 and in 2013. The series aired in Bulgaria by BTV and in the Bulgarian language; Bulgarians know Balki mostly as a Greek. It aired in the Philippines by RPN 9 in its original form, it aired with Arabic subtitles in Kuwait on KTV2 and in Lebanon on Télé Liban (TL). The series aired in Ireland by RTÉ on Network 2 in its original form.

On September 29, 2017, Perfect Strangers became available for streaming on Hulu along with fellow Warner Bros. TV properties Family Matters, Full House, Hangin' with Mr. Cooper and Step by Step, in addition to Disney-ABC TV properties Boy Meets World, Dinosaurs and Home Improvement.

In July 2017, a representative for Warner Archive Collection indicated on a social media post that the remainder of the series would be released on DVD, with a formal announcement to be made in the near Future. The complete third season will be released on April 17, 2018.