When he and Jeff Lynne presented the song to Harrison's record company, the executives insisted it was too good for that purpose, a decision that resulted in the formation of the Wilburys.

[13] In a 1990 interview for the Dutch television show Countdown, Harrison said that he started writing "Handle with Care" – with a section in mind for Orbison to sing – on the morning of the session.

[21] In music journalist Matthew Greenwald's description, the composition is "built around a descending, folk-rock chord pattern and some ... major-key chorus movements".

[24] Author Ian Inglis writes that Harrison's verses reflect his having overcome hardships and challenges throughout his musical career, with the line "Oh, the sweet smell of success!"

Inglis says that while the song bears "Harrison's distinctive musical and vocal signature", the Orbison-sung segments evoke the "lonely" theme that was a defining element of Orbison's work from the late 1950s onwards, just as Dylan's bridges, containing the line "Put your body next to mine, and dream on", capture the "straightforward sexuality" evident in songs from that artist's late 1960s country period.

Having been invited by Harrison to assist with the recording, engineer Bill Bottrell recalled that the garage studio had yet to be set up and the equipment was a mix of seemingly unused items.

[11][24][nb 3] The electric and bass guitars were added to the basic track on the day after the session at Dylan's house,[31] and drummer Ian Wallace overdubbed tom-toms.

[32][33][nb 4] When Harrison presented a mix of "Handle with Care" to Warner Bros., the company's executives insisted that the track was too good to be used as "filler" on a European single.

[37][38][nb 5] On Harrison's next visit to Los Angeles, from 8 May onwards, he, Lynne, Dylan, Orbison and Petty began recording the album Traveling Wilburys Vol.

[6] The Wilburys filmed a music video for "Handle with Care" in early October 1988, at an abandoned brewery near Union Station in Los Angeles.

[43] The band were dressed and styled by Roger Burton, whose stylist credits included the films Quadrophenia and Chariots of Fire, and music videos for David Bowie, Eurythmics and UB40.

[54] According to authors Chip Madinger and Mark Easter, the song received widespread airplay on US radio and the video was given "saturation play" on MTV and VH-1.

3,[62] Elizabeth Wurtzel of New York magazine highlighted "Handle with Care" among the Wilburys' "upbeat, irresistible songs ... that unified the rock audience" in 1988, by presenting the middle-aged stars as a "new act" to young listeners while also finding favour with the babyboomer market.

[65] Matt Melis of Consequence of Sound lists "Handle with Care" tenth in his "Top Ten Songs by Ex-Beatles", saying that the Wilburys showed Harrison "at his absolute best since his solo work in the early Seventies" and, following this first spontaneous collaboration, "The rest is super group history.

With reference to the musical eras represented by Orbison, Harrison and Dylan, respectively, he concludes: "its real significance rests ... on its symbolic fusion of three revolutionary moments in the history of rock 'n' roll that had their beginnings in Sam Phillips' Sun Studio in Memphis, in the clubs and bars of Liverpool and Hamburg, and in the folk venues of New York's Greenwich Village.

"[67] Author Simon Leng views the song as a "worthy hit" that displays the three lead singers' styles to equally good effect and, in the closing solos by Harrison and Dylan, features "two of the most famous instrumental signatures in popular music [playing] in tandem".

[68] In an article covering the launch of the expanded edition of Harrison's autobiography, I, Me, Mine, in 2017, Billboard's Andy Gensler commented that "Handle with Care" remained a fixture on FM radio.

The Wilburys' group dynamic is referred to in the episode, when the character Ari Spyros, a socially awkward compliance officer, shouts "Handle me with care!"

[76] On 14 September 2014, during the BBC Radio 2 Festival in a Day event in London's Hyde Park, Lynne performed "Handle with Care" as a tribute to Harrison and Orbison.

[79] In 2006, Jenny Lewis covered "Handle with Care" on her debut solo album, Rabbit Fur Coat, recorded with the Watson Twins, Ben Gibbard, Conor Oberst and M.

[29] Writing in March 2007, after the announcement that the long-unavailable Wilburys' catalogue was about to be reissued, in the box set The Traveling Wilburys Collection, Whitney Pastorek of Entertainment Weekly said: "while Petty's been doing the tune in concert for years, Jenny Lewis' decision to cover that song on last year's Rabbit Fur Coat seemed to get plenty of hipsters asking, Dude, how come I can't buy the original?

[83] Reviewing the 2016 album and DVD release from the concert, for PopMatters, Megan Volpert wrote: "The gentlemen collaborate with Dhani on the Wilburys' 'Handle with Care', audibly evoking not just the noises of George, but also the ghost of Roy Orbison and almost hilariously good impersonations of Tom Petty and Jeff Lynne ... Dhani could've gotten Petty and Lynne, no doubt – but he is working on something arguably more important here than what Concert for George hoped to accomplish.