"Best Of You" was one of the first compositions for In Your Honor, written by Dave Grohl in his garage following his involvement on the campaign trail for John Kerry. Once the Foo Fighters recorded a demo, they shelved it feeling they could do better. It was only brought back for further production by manager John Silva, who felt "Best of You"'s absence while listening to what they had recorded that far.Taylor Hawkins declared that it was the only song from the rock disc of that album that remained from the original sessions along with "No Way Back".
Grohl stated that while many of his songs start with the music and lyrics come last, the words for "Best of You" were fast to write. Given the Kerry rallies inspired him to do "all these songs about breaking away from the things that confine you", thus came "a song of resistance. It’s about the refusal to be taken advantage of by something that’s bigger than you, or someone you’re in love with. It’s the fight in the face of adversity." Grohl added that "Most people think it's a love song but it's meant to be more universal, which I think is one of the reasons so many people sing along when we play it." The composition had no interest in "an interesting melody", instead featuring "a rhythm that we'd never really used on any of the other albums." The focus was on a strong performance, where Grohl could "scream the whole way through". During the first rehearsals, Grohl came close to injuring his throat and felt afraid of being unable to perform live, but eventually considered he could pull it off as "when you go out and sing words from the heart, you scream twice as hard.”
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 the fire I started."
During the Australian X Factor's fifth season in 2013, eventual series winner, Dami Im opened the Rock-themed Fifth Live Show with a rousing cover of the song and received an unprecedented fifth consecutive standing ovation. Im's performance of "Best of You" debuted at number 78 on the Australian Singles Chart. Having won the series, Im recorded a version for her self-titled album which debuted at number one in the charts and was certified Platinum eventually.
Lena Katina of the Russian pop group t.A.T.u. covered this song in the European Fan Weekend concert in 2013.
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.