Rocksmith is a music game where a guitar is used as a controller to play songs as popularized through the Guitar Freaks, Guitar Hero and Rock Band series. Unlike those games however an actual guitar is used. Almost any electric guitar can be plugged in using a custom standard 1⁄4 in (6.35 mm) output jack of a guitar to a USB plug to transfer the signal from analog to digital. The Real Tone cable is included with every copy of the game but can also be bought separately as the game can be played in split-screen multiplayer. The guitar playing process is not simplified as it aims to teach players to learn and improve real guitar skills. Instead it has an adaptive difficulty level starting with single notes that gradually become more complicated and are eventually turned into the complete riffs if the player manages to keep up.

It borrows the familiar view from the aforementioned games where a song is represented as a stream of notes flowing on a board towards the player. They need to be timed right to play them out correctly. Near the bottom of the screen is a horizontal overlay that shows the correct position on the fingerboard. Near the top of the screen the lyrics flow by along with the overall score based on accuracy and difficulty. An overall rating keeps track of the progress throughout the entire game. It comes with a selection of over 50 classic and modern rocks songs with some unlockables when a double encore is achieved in a journey mode set.

In the amp mode the sounds of the guitar can be tuned through a selection of pedals and amplifiers. They can be mapped to three slots to activate them during songs. Preset settings are used for each song by default to make them sound authentic and custom ones are unlocked when a songs has been properly played. A riff repeater option offers custom difficulty levels by breaking up the songs into parts such as the intro, outro, solo, verse and it comes with three modes. In Free Play every note needs to be played, The Accelerator detects the skill level and adapts based on speed along with the option to define a custom speed throughout the song, and The Leveler starts at the lowest level and offers 30 chances to get it right. Performing well in the latter raises percentages until a riff has been mastered.

Various minigames are offered to practice 12 specific guitar skills such as chords, sustains, shifting, tremolo etc. There are variants of Galaga, a slider puzzle, a baseball game, a "Simon says" game, one where zombies are shot through chords, and more. Next to the solus version there is a guitar bundle that comes with a real Epiphone guitar, picks and a strap.