Hey folks! Reminiscent Cheeseburger here! I'm here to attempt to try to clear the confusion that is plaguing you the readers!
Ah! First off though, if you're new to Dorohedoro (read only a couple ch.) be braced for spoilers, as I'll be dropping them like a chicken drops eggs.
Okay! Let's start from the beginning! Our story takes place in a city called hole, (could be the world as well for all I know) where 1. There are constant attacks on Hole by transdimensional magic users who practice there magic. 2. A mall that is placed over a radioactive / magical swirling torrent of liquids, basically a toilet. 2 1/2. The magic swirl animates corpses, and is strongest in the mall (note happens only on 1 specific day). 3. There is a hospital where an ageless doctor treats magic victims. 4. Our MC's are The Lizard guy, and the Blonde girl, the lizard guy slightly more so (as all the shit revolves around him). 5. So the lizard guy is cursed, and doesn't remember anything of his past life, and why he is transformed into a lizard man, due to the nature of his curse, he hunts down magicians and sticks them down his throat because...he's a pervert, no not really, he does it because he's got a magic curse down there who he asks if the magician is the one who cursed him, showing that his goal is to reverse the effects of his curse, oh and he works part time at that magical treatment hospital. Simple right? That's pretty much our base setting.
Okay! Get ready to wade through the shit with me on this. Sooo after that 2 randoms (magicians) come to Hole to practice there magic. Lizard man kills one, and the other runs away through a magic gateway. Surprise they're not just any weaklings, they're the retainers of En, the man most favored by the Devils. (Did I not explain Devils? Well apparently the magic world is like a level above the underworld, and I'm guessing that's where there magic comes from, oh and magicians can become devils through intensive training btw) Where was I? Oh yeah... So retainers, the living guy reports to En that the guy was big scary, and has crosses on his eyes. Yes cross eyes are a gang of magicless individuals who live in the magic world, tired of being abused and looked down upon they joined the cross eyes gang where there boss provides black cocaine that gives non magic users magic temporarily, making the cross eyes a formidable force. In flashbacks En loses people and things to the cross eyes, back then he wasn't super famous. He confronts the cross eyes boss, and is practically defenseless, but due to the cross eyes' boss screwing up with his magic, he disappears, and En is crowned hero of the world, also showing why he has a hate for the cross eyes, which he continues to hunt down. Which explains why he trys to kill the Lizard man.
Okay. So the Lizard man is actually a former resident of Hole. Wanting magic, he did some weird shit with a "little devil" (a thing in every magic users head that grants them magic), and disappeared, everyone thinking he died. Well he didn't, he also went on to have about half a dozen personalities, including the boss of the cross eyes, and the only friend to the magician who cursed him, who he later killed as the personality of the cross eyes boss. The cross eyes boss is so fearsome, because he would remove the devils in magicians heads to steal there powers, explaining why he killed his other personalities friend, getting him cursed in the 1st place.
When the Lizard man disappears, En becomes interested in the blonde chick, who it turns out is actually a magician, but doesn't know her own power, which is time traveling, so En kidnaps her and attempts to make her his bride. She gets away with the help of a devil friend of hers, and searches for the Lizard man. The cross eyes gang takes over Ens' manner, and I don't remember how, but En dies (the En family wish to get there hands on his "little devil" so that they can resurrect him) The cross eyes boss comes back out of no where, and is creepy and mysterious as can be. He consumes to many of the "little devils", and turns into this big black thing that ooses the black magic powder, or as I call it black cocaine, and apparently eats people, and he somehow is teleported to Hole. Meanwhile the blonde chick begins training to become a Devil, trained by her Devil friend who had his powers stripped for helping her, she also learns the dangers of her time traveling abilities. Meanwhile meanwhile the magic doctor guy in Hole is actually the husband of a Devil, and is hosting the En family in Hole while they hunt for the big black monster tentacle thing that the Lizard man has become (non-sexual in every way).
There's a couple things I left out like individual characters of the En family, who for the most part play comical roles, or are non-essential till En "dies", and the guy who cursed the Lizard man is also important, but I'll leave him out, as well as the leaders under the boss of the cross eyes. And why people walk around with masks, needless to say those people are blessed to be noticed by a powerful Devil.
Anyone want to add something be my guess, but this was the best summary I could come up with.