Soul Eater primarily revolves around students classified as meisters at the Shinigami Weapon Meister Vocational School or Shibusen for short, located in the fictional Death City, in Nevada, United States. The school is run by Shinigami, the God of Death himself, as a training facility for weapons and the human wielders of those weapons, the meisters. Each meister has at least one demon weapon companion which has both a weapon and human form. Shinigami created the school as an organization that enforces peace in order to prevent the rebirth of the "kishin", the evil demon god that nearly destroyed everything by plunging the world into chaos. Human souls that have become evil by straying from the path of humans have a high risk of becoming kishin, so evil humans are constantly being hunted down and killed by the students trained at Shibusen.

The ultimate goal of the students with their weapons is to have their weapons defeat and absorb the souls of ninety-nine evil humans and one witch, which will dramatically increase the power of the given weapon and thus be capable of being used by shinigami. In order to ensure this is done in a timely manner, all students and weapons attend classes regularly and are given homework or supplementary lessons to further their training. The meisters have a rating system that goes from one to three stars which usually measures soul energy. It is important that the meister and weapon can tune their "soul wavelength" to perform high level attacks and bring out the weapon's full power.

Maka Albarn is Soul Eater Evans' meister. She is the more level-headed of the two but when her anger gets the better of her, she will put her foot down. Where Soul Eater seems to be the brawn, Maka is the brain. She always tries to think of a way to beat their opponent by exploiting the opponent's weaknesses. Soul Eater, or simply Soul, Maka's Demon Scythe partner, has a personality which mainly consists of what he considers "cool". Being a "cool" guy, he almost always uses the direct approach which most of the time fails. He sometimes becomes too driven by the idea of eating souls, which leads him to bicker with Maka, but in the end they remain friends and partners.

Maka is friends with a meister named Black Star who is Tsubaki Nakatsukasa's meister. He comes from a family of ninjas known as the Star Clan, and uses ninja tactics during battles. His biggest weakness is that he is a total show-off and thinks that he is some kind of star, which he happily proclaims, defeating the purpose of the ninja arts. Black Star hates it when someone gets more attention than him and is determined to show them who the real star is. He is also able to use his soul wavelength in hand-to-hand combat. Tsubaki, Black Star's Dark Demon Blade partner, can change into multiple ninja weapons when in battle. She is considered a "tool" like weapon since she is able to transform into different types of weapons, unlike the others. She is most of the time disheartened by Black Star's loud (and often obnoxious) antics. Despite this, she quietly puts up with his mistakes because she likes his brave and bold attitude. She has a very forgiving personality and always tries to help everyone even when she has no idea how to help.

A third meister, Death The Kid, is Patti Thompson's and Liz Thompson's meister and Shinigami's son. Otherwise known as simply Kid by his friends and family, he is completely obsessed about everything being symmetrical and takes the idea of perfection to the extreme, which seems to indicate that he has obsessive-compulsive disorder. To him, anything symmetrical is beautiful and if it is off by any measurement, he will try to correct it right away. Showing Kid anything that is too asymmetrical or mentioning his hair will send him into a state of massive depression (which normally takes encouragement from Patti and Liz to break). Patricia and Elizabeth Thompson, commonly "Patti" and "Liz", are Death The Kid's Double Team Demon Pistols. Patti is the younger of the two and is naïve compared to her more mature older sister Liz. She and her sister used to live on the streets of Brooklyn before being found by Kid. Both Patti and Liz admire Kid's dignified soul, due to their being from the streets. Even without Kid around, they are able to use each other's transformed state as a single gun, switching places to avoid attacks.

In Soul Eater, the characters can use certain techniques during battle that revolve around a given person's "soul wavelength", which, as the name implies, is the wavelength of one's soul. By using their soul wavelengths, a meister and his or her weapon can pull off a more powerful attack by performing a "soul echo" which matches their soul wavelengths. When the soul echo is used to its maximum level, it becomes known as a "soul resonance" which allows the partners to use high-class attacks. These include the "witch hunt", which causes the given weapon to grow and cut through the air for long range attacks; the "sorcerer hunt", otherwise known as the "witch hunting's witch hunt" which is a more powerful version of the witch hunt attack; a stronger version of the witch hunt known as the "demon hunt"; and the "protective spirit body", which creates a large shield for defense against attacks by fusing the soul wavelengths of the partners. A powerful, and rare technique known as the "soul purge" enables the user to send his or her own soul wavelength through one of their hands to directly damage the opponent's body; when using both hands, which deals twice as much damage, the technique is known as the "double soul purge twin lance". A stronger form of the soul purge is known as the "soul menace". Other techniques include the "soul feedback" which is used to find the presence of others, or the "soul protection" which is a magical barrier used by witches to hide their soul wavelength from others allowing them to blend in with normal humans.

Maka Albarn:
Maka is Soul's meister. She is the more level-headed of the two but when her anger gets the better of her, she will put her foot down. Where Soul seems to be the brawn, Maka is the brain. She always tries to think of a way to beat their opponent by exploiting the opponent's weaknesses.

Black Star:
He is Tsubaki's meister. He comes from a family of ninjas, which explains the star on his shoulder. He uses ninja tactics. His biggest weakness is that he is a total show-off and thinks that he is some kind of star, which he happily proclaims, defeating the purpose of the ninja arts. The few times he uses his ninja stealth is when he peeps on Tsubaki when she is bathing, or when he finally takes the fight seriously.

Death The Kid:
He is Patti and Liz's meister and the Shinigami's son. He is called Kid by his friends and family. He suffers from obsessive-compulsive disorder, which is represented as a complete obsession about everything being symmetrical and takes the idea of perfection to the extremes. To him, anything symmetrical is beautiful and if it is off by any measurement he will try to correct it right away, even if the situation calls for utmost attention. The biggest problem Kid has is with his hair because one side being completely black while the other has three white strips going across it.

Ox Ford:
Ox is one of the top students at Shibusen in terms of grades and is Harvar's meister. He is named after the University of Oxford. He calls himself the "Skilled General Lightning King" a fact that annoys Black Star because they are two different titles 'King' and 'General'. He also has one-sided feelings for Kim. Later in the series when he attempts to rescue Kim from Arachnophobia and displays his sincere adoration for her, Kim starts to reciprocate his feelings.

Kilik Lunge:
Kilik is a pot meister and is often teamed up with Ox for missions. Kilik uses a pair of twins as his weapons, Pot of Fire and Pot of Thunder. Though termed "pots", they resemble large gloves in their weapon form. Out of weapon form they resemble two small girls with blue eyes. Kilik also seems to be pretty agile, having the second best running time in Shibusen after Black Star.

Kim Diehl:
Kim is a lamp meister and partner to Jacqueline. She is the object of Ox's affections but she constantly turns him down. Kim is obsessed with making money. Kim and her weapon are allied with the Arachnophobia, a group that serves the witch Arachne, though this is not entirely be her choice. It is reveled that Kim is a witch that wanted to get away from the witches' assembly and lifestyle and thus became a Shibusen student. Her partner knows she is a witch, but sticks by her all the way.