In an interview discussing the band's successful singles, Dave Grohl notes that:
"Best of You" is funny because we demoed so many songs for In Your Honor, I'd kind of forgotten about it. Our manager came in and said, "What happened to that 'Best of You' song?" So we pulled it out and worked on it a little more.
The music video was directed by Mark Pellington, best known for his work on the video for "Jeremy" by Pearl Jam. He was inspired by the death of his wife a few months prior to the shoot, and was drawn to the song's notion of dealing with pain in life.
The video features the band playing on top of the abandoned Linda Vista Community Hospital. Along with the band's scenes are clips that show pain, depression, or anger:
Clips with children playing alone or with each other, one scene shows one girl hugging another.
A car crash
A lion pouncing on its prey, which is a vulture
A snake attacking a rodent
A zebra kicking another zebra behind itself
A snarling wolf
Crash test dummies being crushed by a car crash test
Men and women showing affection for each other.
A nuclear explosion
A baby crying
A wall covered in writing, including the phrases "Help me" and "They all died in a fire I started."
Stereophonics covered the song on BBC Radio 1 during the Live Lounge sessions in 2007 *Prince covered the song during the halftime show at Super Bowl XLI in Miami, Florida, on February 4, 2007. Drummer Taylor Hawkins expressed surprise by the performance, due to Prince's prior criticism of the band's desire to release a cover version of his song "Darling Nikki" in 2003.
Anastacia covered the song for her fifth studio album It's a Man's World. The song was released as album's second single, only in Austria, Germany, Switzerland and Italy. The music video was filmed in Barcelona, Spain in October 2012.