Monstro appear as a large, fleshy lump with round, beady eyes and pale-skin. The most noticeable-known feature is a cleft-lip that sports with a wide mouth with 6 crooked teeth (one from the left is larger than the others) and large teeth gums. He also appears to be missing one of his teeth from the left side. His large tongue can be seen while spitting out bullets.
He will semi-randomly switch between hopping towards the character, spitting a burst of blood tears (noticed by his "about-to-sneeze" expression), or launch into the air and land at the spot the player was standing in when he went up along with blood shots fired in many directions when he hits the ground.
- The distance between the character and Monstro will not influence the attack he will choose, he switches between them at will. Therefore, they'll want to stay at medium range to retain maximum flexibility. The blood shot spray looks nasty, but the shots have arcs that often go over their head.
- It's also possible to circle around Monstro while staying at a short distance. This way, they don't have to worry about his shots, but his small leaps become a bit more dangerous.
- Despite his bulk, Monstro moves around a fair bit; area of effect items (like Mr. Boom, Lemon Mishap, or Doctor's Remote) will not be very effective unless they get lucky on placement. Doctor's Remote, however, works somewhat well as the player can use mouse clicks to stay on target with Monstro. Try to wait until he launches into the air, then move and aim where they were standing when he lept. Use his shadow to track where he will land.
- Regular bombs take large chunks out of his health, but if he decides to launch you may end up wasting the bomb. An easy way to use area of effect items is when Monstro makes a huge jump, he will land approximately at your last position before he jumped, so just use the item before moving.
- If Isaac is down to one heart, avoiding damage becomes a number-one priority as some of Monstro's shots (the bigger ones) can deal up to a full heart of damage.
- For some people, it's hard to tell where he is when jumping in the air, so homing shots can help to predict his landing. Isaac can sometimes tell by the shadow that Monstro's body makes in where he will land, but mainly, he only lands where Isaac current position was/is.
- It's possible to run underneath Monstro while he is "hopping". This can make shooting a bit easier.
- Pay attention. If Monstro uses his blood spray while Isaac is cornered, look for an opening. There's an opening in every barrage Monstro throws at him, so use this to Isaac's advantage.
- Health: 112.5
This version is much smaller and has less health. An additional Monstro shows up, and you'll have to battle both of them simultaneously. In boss rooms, there will be two and in normal rooms in later levels, one will be added to the amount that would spawn in the room by default. Obviously, when smaller, it's harder to stay still and maintain fire, and with two or three of them present, it's best to run in a circle around them and never fully stop moving unless they're both just hopping around.
- HP: 312.5
This champion is slightly larger and has more health. He can't launch himself into the air, and uses his shot attacks much more often.
In the Eternal Edition for the original game only.
Eternal Monstro appears larger, moves and attacks twice as fast and shoots more projectiles. It's capable to "duplicate" - split into 2 half-sized Eternal Monstros once 1/2 of its health is taken away. The same thing can also apply to those smaller Eternal Monstros, causing them to split again and become 1/4-sized. It's possible to make one Eternal Monstro split into a maximum of 4 small Eternal Monstros in one room. Half-sized Eternal Monstro acts the same as normal Monstro, and the 1/4-sized Eternal Monstro acts like the Grey variant.
- If the 2 half-sized Eternal Monstros are killed simultaneously, each of them will spawn 3 smaller Eternal Monstros.
- If Eternal Monstro is killed by II - The High Priestess, it won't split and count as a normal boss kill, which means no Eternal Hearts will be dropped if Eternal Monstro is killed in this way.
- Monstro appears in the original game's demo.
- From one of the sketches of the artbook, Monstro was going to possess with 8 teeth rather than 6 while still missing one of his tooth from the upper jaw.
- Monstro possesses a cleft lip, or "harelip", a common birth defect.
- The name Monstro means "monster" in Portuguese.
- It is also a somewhat mispronunciation of the Spanish word "monstruo".
- According to Edmund McMillen from the artbook at page 1, Monstro is referred as "Gish with a hairlip", meaning that Monstro is based on the playable character from Gish, one of Edmund's previous games.
- One of his teeth is missing, possibly referring to the item Monstro's Tooth, however said item is disabled when fighting him.
- From the artbook at page 10, Monstro's attack after smashing to the ground is a 8-way bullet attack rather than bursting ones. This attack method was never displayed and later used for his posthumous counterpart Monstro II.
- Monstro's appearance and behavior is very similar to SnackOLantern, a main character of a mini-game by the same name posted by Edmund on Newgrounds in 2003.
- From the concept art where it feature early concepts of monsters, there is a monster highly resembles to that of Monstro and was going to be called "Hairclip". It didn't made it to the final game's release, however.
- From the original game, it is possible to have Monstro shove the character out of the boss room. If he lands on them when they're next to the boss door, they can sometimes clip through it. This was fixed from the Wrath of the Lamb DLC.