The brothers grew up in the 1990s in an Orthodox Jewish family in Brooklyn. The Fine Brothers stated that they have been making videos almost their entire life; Benny, being the elder brother, would "rope [Rafi] into making all kinds of weird stuff." New York detailed the two "started recording comedy sketches as adolescents, when they got their first video camera." They spent most of their teen years in Sullivan County, New York. Benny started college at age 15, while Rafi attended Dickinson College for two years before transferring to Hunter College, where he got a degree in film studies. The two began entertaining their friends with short sketches and full length comedies shot with action figures.

The brothers stated that they created a live action feature in 2000 that made its way into comedy film festivals, and that they were planning to create a feature each year, hoping that one feature would soon help the brothers break into Hollywood. Despite winning young filmmaker awards, they soon came to the conclusion that this method would not be the best path, and decided their Future would be on the internet, which they viewed at the time as the new film festival. The brothers created their first website in 2003, and uploaded their first web video in 2004. They broke their features into 10-to-15-minute chunks to showcase the feature to an audience. The brothers used their website and early online works as a discoverability tool that would launch them into traditional film. In 2004, the brothers created a feature-length live-action comedy, titled G.I. Joe: The Epic Saga, before beginning to upload more Sketch and comedy content onto websites such as MySpace. The duo then moved from Orlando, Florida to Los Angeles, where they continued to upload more videos on their YouTube channel, which was created on June 4, 2007. New York wrote that the two entered the YouTube community as "low-paid video producers for other companies, but kept making their own videos on the side." Their earlier videos contain mature social satire humor.

The Fine Brothers created a show titled Lost: What Will Happen Next?, which is a parody show based on Lost. The show debuted on January 24, 2008, and was the first long-running series on the Fine Brothers channel. The show lasted 19 episodes and ended on November 1, 2010. The show featured several characters from other fictional universes such as the Avatar and Star Wars universe. The Fine Brothers collaborated with Rhett and Link to create a parody song of Lost as well.

The two soon joined the Maker Studios venture, and stated that after speaking with Shane Dawson about a plan for the project, "we were the head of production and head of creative." The duo ran Maker Studios throughout 2009 and were responsible for the early success and planning for what became known as Multi-channel networks (MCNs)—they have since been vocal advocates for fair treatment of creators by the networks.

The Fine Brothers launched a series titled Kids React on October 16, 2010, the first video being "Kids React to Viral Videos #1 (Double Rainbow, Obama Fail, Twin Rabbits, Snickers Halloween)". The Kids React series features The Fine Brothers, off-camera, showing kids several viral videos or popular YouTubers and having the kids react to the videos.

The Fine Brothers are the creators of MyMusic, a sitcom show funded by YouTube's $100 million original channel initiative. MyMusic features a main ensemble cast of Adam Busch, Chris Clowers, Jack Douglass, Tania Gunadi, Grace Helbig, Lainey Lipson, Jarrett Sleeper, Mychal Thompson and has featured many guest stars, with members of both Kids React and Teens React also appearing. The series has an interactive transmedia aspect, which the Fine Brothers have spoken on, saying "To us, new media should be 'new' – and just not just a passive experience. The ability to create new storytelling elements and new ways to entertain audiences is what is so motivating about being a creator at this time." The show revolves around MyMusic, a company led by CEO Indie (portrayed by Adam Busch) who is portrayed as a stereotypical modern-day hipster. Another character on the show, Metal (portrayed by Jarrett Sleeper), is based on the brothers' teenage years. "The Metal character comes directly from us when we were teenagers. We were metal heads, full-on," as Fine stated. MyMusic has a separate channel on YouTube from the main Fine Brothers channel (MyMusicShow), which had over 381,000 subscribers and 28.9 million video views as of July 7, 2013. MyMusic was nominated for nine Streamy Awards in the 3rd installment of the event, with three of the nominations going to the Fine Brothers. The second season premiered on August 20, 2013.

On April 30, 2014, it was announced that a spin-off of the Fine Bros' React series called React to That was going to be aired on Nickelodeon. The Fine Bros stated in an episode of Fine Time that they plan on continuing to upload YouTube videos consistently, however. The show aired 12 episodes. They also created and host the TV series Six Degrees of Everything that aired on TruTV in 2015. In early 2016, New York detailed that their company employed around 50 people.

On January 26, 2016, the Fine Brothers announced that they would license and trademark their existing React series and let creators create their own react series. In particular, the Fine Bros applied to trademark, among other terms, the term "react", which is used in the title of numerous other YouTube videos unrelated to the Fine Brothers' YouTube channel. The announcement was met with backlash from some of their viewers and fellow YouTube content creators, many of whom believed the Fine Brothers were attempting to prohibit the creation of reaction videos by people unaffiliated with their channel. In response, the brothers promised that they would "not be trying to take revenue from other types of reaction videos, and will not be copyright-striking." However, other YouTubers reported copyright related takedowns of videos containing Fine Bros footage. There were also reports that another YouTube channel had produced "Seniors React" videos just prior to the Fine Brothers' "Elders React" series. The backlash led to a dramatic drop in subscribers, with upwards of 675,000 accounts collectively unsubscribing from the React and Fine Bros Entertainment channels in protest as of February 22, 2016.