The single reached #45 on the Billboard Hot 100 chart, #2 on the Billboard Mainstream Rock Tracks chart, #21 on the UK singles chart^[2] and #3 on the ARIA Chart.^[3]

The song received a highly positive retrospective review from Allmusic journalist Matthew Greenwald, who described the song as "one of the most memorable records of the 1980s." Greenwald wrote: "Musically, the song is built around a descending, folk-rock chord pattern and some fine major-key chorus movements. George Harrison handles the verses, and there are also two excellent bridges featuring Roy Orbison and Bob Dylan. Orbison's section capitalizes on his awesome, operatic vocal pipes, and the effect is wonderful."^[4] The opening chords are reminiscent of Jeff Lynne's "10538 Overture", the ELO single from 1972 and Paul Weller's, "The Changing Man".

The song was originally intended as the B-side of Harrison's "This Is Love". Harrison had not yet written a song for the B-side when an impromptu gathering of the musicians who became the Wilburys turned into an informal songwriting and jam session. Casting about for a song idea while relaxing in a garden near Bob Dylan's recording studio, Harrison was inspired when he noticed a box in Dylan's garage that was labelled "Handle with Care". The box also inspired the opening line: "been beat up and battered around." The complete song quickly followed, with different members of the gathering contributing various lines. The group moved to a recording studio and quickly laid down the basic tracks which were later polished by eventual Wilburys producer Jeff Lynne. The song depicts a conversation between a man and his new found love wherein he is recounting life's experiences which have affected him, contributed to his loneliness, and his plea to his love to "handle me with care" because of all the things he had been through.

Harrison's record company decided that the song was too good to be released as "filler." Encouraged by this response and the enjoyable experience of recording together, the group re-convened to record the first Wilburys album, which featured "Handle With Care" as the lead track.

The music video for the song features all the group members performing the song in an abandoned building while standing around an old-fashioned boom microphone, with drummer Jim Keltner in the background. There are brief cutaways to show still photos of the singers as children or young teens.

The song was the last release and video for group member Roy Orbison prior to his death on December 6, 1988...