Damage

Damage refers to the amount of damage each tear deals to enemies, and is represented by a sword. As damage increases, the size of the tears increases as well. However, tear size is not always a valid indication of how much damage your tears will do. Tears will grow and shrink when your damage changes, but tears of a certain size do not have a specific damage value, and two tears of the same size (in two different runs) are likely to have different damage values.
 * is an example of an item that provides a very high Damage stat.

Effective Damage
The formula for damage is: $$\color{white}\mathit{EffectiveDamage} = \mathit{CharBaseDmg} \times \sqrt{\mathit{TotalDmgUps} \times 1.2 + 1} + \mathit{FlatDmgUps}$$

where:
 * CharBaseDmg = The character's base damage multiplied by their multiplier,
 * TotalDmgUps = the total of all regular damage ups collected (not including special exceptions or damage multipliers),
 * FlatDmgUps = the total of all damage ups that are excluded from the above (for example, Curved Horn or ), and
 * EffectiveDmg = the approximate damage that can be expected per tear, or per 'tick' when using or.

This formula makes most damage upgrades less potent the more that Isaac has. For example, a Pentagram on Isaac would make his total damage (1 * 1.2 + 1)^0.5 = 1.48 * 3.5 = 5.19. Another Pentagram increases this to 6.45 (a 1.26 increase instead of a 1.69 increase). The higher a character's base damage, the more effective damage ups will be for that character. Flat damage modifiers and special adjustments like or  happen after the main formula.

Character Modifier
The character base damage is defined by a base number and a multiplier.
 * †: 0.75 • 3.50 = 2.625
 * 1.00 • 2.75 = 2.75
 * ,, , , , , , , , : 1.00 • 3.50 = 3.50
 * 1.05 • 3.50 = 3.675
 * 1.00 * 3.75 = 3.75
 * ,, and : 1.20 • 3.50 = 4.20
 * 1.35 • 3.50 = 4.725
 * 1.50 • 3.50 = 5.25
 * 1.50 • 3.50 = 5.25
 * 2 • 3.50 = 7.00

†: has the unique effect of increasing Eve's damage modifier from 0.75 to 1.00 when active. This does not apply to other characters, however.

Damage Multipliers
Some items multiply damage rather than simply adding to it. Damage multipliers do not simply multiply the character's damage once; the damage stat is constantly recalculated and the damage multipliers are multiplied with the end result. This means that if a character starts with 3.50 damage and gets a 2x multiplier, their effective damage will be 3.5*2 = 7.00. If an item that grants +1 damage is picked up, the character's effective damage will be 3.5*(1*1.2+1)^0.5*2 = 3.5*(2.2)^0.5*2 = 3.5*1.48*2 = 10.38, and not 7.00 + 1.

Most damage multipliers stack; for example, and  both provide a 2x multiplier; picking up both will give a total multiplier of 4x. The exception to this is the 1.5x damage multipliers provided by, , and the combination of and. These multipliers do not stack; for example, picking up both Cricket's Head and Magic Mushroom will result in an overall 1.5x multiplier rather than the expected 2.25x.

Reverse Formula
Consequently, the reverse formula to determine your damage bonuses from the displayed value is $$\color{white}\mathit{Bonus} = \frac{1}{1.2}\left[\left(\frac{\mathit{EffectiveDamage}/\mathit{Multipliers} - \mathit{FlatDmgUps}}{\mathit{CharBaseDmg}}\right)^2 - 1\right]$$ Multipliers is the product of all damage multipliers in effect.

Other

 * In co-op, Rage Baby, Revenge Baby, and Belial Baby will occasionally briefly increase damage. Dark Baby will occasionally briefly increase all stats, including damage. Buddy Baby will occasionally briefly grant the effect, which increases damage. Whore Baby will occasionally briefly grant the  effect, which increases damage.
 * activates the effect for the current room, which increases damage.
 * activates the effect for the current room, which increases damage.
 * activates effect for the current room, which increases damage.
 * consumes all pedestal items in the room and turns them into random stat upgrades. No effect on shop items.
 * increases damage, range, and Isaac's size for the current room.