The actual song is about the fall of Babylon from the Book of Revelation, (particularly chapter seventeen) from which many quotes are taken, such as "Seven headed beast, ten horns raise from his head", "hatred strips her and leaves her naked", and other references. The Harlot referred to in the song is Great Babylon, quoted in the song "Fallen now is Babylon the great." On Avenged Sevenfold's All Excess DVD, Tony Petrossian,who directed the video, says that M. Shadow's lyrics for this song about the fall of Babylon is comparing Babylon to Hollywood, showing many Hollywood clichés such as the young, innocent boys being corrupted and losing their souls. In the music video the Harlot was played by actress Elizabeth Melendez.

The song is one of the first songs recorded with singer M. Shadows' different vocal style avoiding unclean vocals as well as a more hard rock sound as opposed to their previous work, with heavy and fast riffs and a relatively normal song structure (with the exception of the guitar solo, which comes after the first chorus rather than the second, atypical of a three verse song).

The song's rapid main riff was voted as the 14th greatest riff ever by the guitar magazine Total Guitar in March 2007. Total Guitar wrote: "The main riff to Beast and the Harlot is a great piece of dropped-D riffing with Zacky and Synyster cleverly placing the second part of the riff across the beat to create an aggressive syncopated feel, once again avoiding all the usual metal clichés."

The song is featured in the soundtrack of the video games Burnout Revenge, Guitar Hero II, Guitar Hero Smash Hits and the upcoming Rock Band 3. The version in Guitar Hero II is a cover version, while Smash Hits features a master recording. The song was also featured in The Real World Road Rules reunion. The cover art for the single of the song was done by Avenged Sevenfold's close friend Cam Rackam.

Shadows and the songwriting crew drew heavily from Biblical literature, history, and old literature, including, as previously mentioned, segments of the Book of Revelation, as well as Dante's Divine Comedy of Hell. Historically, the sexually deviant queen of Babylon provided the basis for the song, as well as the recurring theme of sexual temptation in the music video.

The seven headed beast with 10 horns, which is referred to many times in the song, is the anti-Christ. Since Babylon collapsed, ("fallen now is Babylon the great") presumably because of its moral deficiencies, it can be assumed that Dante and Shadows were correct.

The black tar which represents the departed soul in the corrupted victims in the video is derived from Dante's 5th Malebolge in Hell. The demons wreck the sinners (in that case, those who betrayed the church) with hooked spears.