One of the major differences within the Manga and the Anime is the type of people who are able to consume souls and how one achieves a Death Scythe status. In the manga, one must collect nintey-nine Evil Human Souls and one Witch Soul. Those Souls are on a list made by Death and specify who is allowed to be hunted in DWMA. However, the anime introduces the Kishin Egg concept, leaving it up to the student's ability in Soul Perception to find Kishin Souls and hunt them down.
Characters such as White☆Star, Jack the Ripper, Don Al Capone, and Lupinin the manga are wanted for crimes such as murder and thievery and did not consume souls, whilst in the anime, they also took souls. The Kishin Egg's concept is inconsistent with the anime, as Death explained during the DWMA anniversary that only Demon Weapons can consume souls. However, non-demon weapons have been seen on screen only in the anime consuming souls. Asura is the exception because he was able to consume Vajra and gained the ability to consume souls. This may be because of his Shinigami nature and some sort of resonating between Asura and Vajra.
Much of Blair's perverted behavior is toned down in the anime.
In the manga, The Little One that Crona kills when they were little was a baby bunny. However, in the anime, the Little One is a small black dragon. This may have been done for censorship purposes.
Auntie has a larger role in the manga, but she only has two cameos in the anime.
In the manga, Marie is pregnant with Stein's child and they are shown to be close. In the anime, while Marie has strong feelings for Stein, she doesn't bear his child in the storyline.
In the manga, it is mentioned that Mifune has a Strong soul equivalent to ninety-nine souls. This is never mentioned in the anime.
Joe Buttataki's role in the anime is different in the manga; in the anime, he was there to build the device to allow the use of Brew (Oceania Technology Development Adviser), while in the manga, he was there to look for a spy (Internal Affairs Investigator). His relationship with Marie as his ex-girlfriend is also not shown in the anime.
Excalibur's past with King Arthur is only included in the anime, not in the manga. Arthur was, however, mentioned in the manga.
White☆Starin the manga was killed by unspecified DWMA agents. In the anime, Mifune is the one who killed him.
In the anime, Maka reveals that her mom gives her postcards as she traveled around the world, but in the manga Maka doesn't specify her fate after divorcing Spirit.
Death, in the manga, dies and his powers are inherited by Death the Kid, who becomes the next Shinigami. However, in the anime, Death is badly wounded by Asura in battle in the Death Room but he survives his wounds. Because of the fate of Death in the anime, Death the Kid doesn't become the next Shinigami. Also, Asura never fights Death a second time in the manga.
The fight in the Death Room was the only time in the Soul Eater universe that the audience sees Death and Spirit fighting together as Weapon and Meister.
In the ending of the manga, and following the deaths of Medusa and Death, the Witches and DWMA end their war and Death the Kid vows to never make anymore Death Scythes. This ending in the anime has never happened.
Justin Law betrays DWMA, joins Asura, and is killed on the moon by Stein and Marie in the manga. In the anime, Justin stays loyal to DWMA and isn't killed.
Mosquito was not defeated by the trio of meisters and their weapons during the battle on Lost Island in the manga, one of the first very drastic deviations. In the anime, Maka uses the Genie Hunter to reduce him to a head and he escapes with "BREW".
Mifune is killed by Black☆Star in battle at Baba Yaga's Castlein the manga in the Operation: Capture Baba Yaga's Castle Arc chapter, but in the anime Black☆Star only wounds him, sparing his life and allowing him to become a teacher at the academy.
In the manga, following Mifune's defeat, Black☆Star chooses to follow the Path of the Warrior like Mifune and strives to be a Warrior God. However in the anime's timeline, Black☆Star chooses a path of his own. In return, he gains the Red Uncanny Sword.
Angela Leon is taken into the care of DWMA following Mifune's death in the manga, but, in the anime, Mifune continues to look after her.
Kim Diehl is revealed to be a witch in the manga and is forced to work with Arachnophobia and later is saved by Ox Ford and Harvar D. Éclair, but in the anime she is not revealed to be a witch. However, the audience's discovery of her witch status is made in the Soul Eater NOT! anime adaptation. Arisa and Risa are also revealed as witches and spies for Arachnophobia. In the anime, they aren't spies and also help DWMA along with Blair by assisting Joe to creating the Death City Robot.
Crona's fate differs in the manga and anime. In the manga, Crona remains an antagonist for much of the series until the end, in which they sacrifice their own freedom to trap Asura. In the anime, Crona works up the courage to fight Medusa but is nearly killed. However, they survive and they are implied to have moved back into DWMA as a full time student.
The anime also hints that Crona moved in with Maka and Soul in their apartment.
Asura, in the anime, was hiding in a Buddhist temple in Tibet when Arachnophobia located him. In the manga, he was hiding on The Moon.
Joe is killed in the manga by Justin after nearing the completion of his investigation, but in the anime, he completes the preparation of the Death City Robot and isn't killed.
Mosquito is killed by Noah (Greed)in the manga but since the introduction of Noah doesn't take place, Mosquito survives the battle between Arachnophobia and DWMA. Giriko also survives in the anime after its destruction, but is killed in the Salvage Arc by Maka and Soul Eater.
In the manga, Asura is defeated by Maka using the Kisihn-Hunt which causes him to bleed and Crona using Brew and the Book of Eibon to seal them both away on the moon in their Black Blood. However, in the anime, Asura becomes too powerful to be destroyed by the anime's variant of the same move. It is Maka's persistence and bravery that gets him to the point that he relapses back into fearful paranoia before he explodes after being punched in the face by Maka channeling her courage into her fist.
Asura is known to be alive under the Black Blood surrounding the moon in the manga. However, Asura's soul is seen being buried, confirming he is dead in the anime adaptation.
For the destruction of Arachnophobia in the manga, Medusa's main role is to use DWMA for her own purposes. In the anime, DWMA's main objective is not to destroy Arachnophobia but to capture Asura. As a result, Baba Yaga's Castle is damaged beyond repair as a result of its battle with the mobilized Death City. Baba Yaga's Castle and Death City are only mobilized in the anime, Death City has the ability after acquiring BREW after Death meets Eibon to redeem himself for listening to Arachne.
Little Ogre and the Black Blood within Soul are removed when they leave Asura's body when they attempted to save Crona in the manga. In the anime, Little Ogre grows and takes over Soul when they are battling Asura. However Maka is able to enter Soul's mind to rescue him and shrink Little Ogre to his original size. Afterwards, Soul accepts the Little Ogre as a part of himself, and then eats him whole. This is the ogre's last appearance as it is most likely that he "died" and the Black Blood was now in Soul's complete control.
In the manga,Hao and Raid begin to look up to Anya after she beats them in a fight and take advice from her to improve themselves, culminating in Raid getting a step closer in mastering his transformation. In the anime they get no development whatsoever.