In every Uncharted game, Nathan Drake's health is represented via the color of the screen. When Drake is injured (by enemy gunfire, explosions, melee attacks and many other things in the cruel world that Drake lives in), the screen will drain of color. When it is completely drained of color and greyed out, Drake is either dead or very close to death; in the latter case a heart-beat sound effect will be made audible.

Health is conserved and regained by avoiding damage. After a few seconds of not taking damage, the screen will return to full color and Drake (or your multiplayer character) will be back at full health.

Depending on the difficulty selected, Drake can take a smaller or greater number of hits before dying, which changes the strategy the player must use in certain locations. On Crushing and Brutal, it only takes a few hits for the screen to get greyed out, and sometimes an attack will be an instant death for Drake.

Outside of combat, many hazards can kill Drake, draining the screen of all color in an instant. Few hazards exist that only injure Drake, but in these cases his health will restore shortly after. Rarely, certain deaths do not drain the screen of color.

In the single-player mode of each game, neither Drake he nor his allies bleed when shot at during gameplay. Most injuries to these characters in gameplay do not show bleeding either, but one exception to this is in Drake's Fortune, where descendants can maul Drake; on Crushing and lower difficulties, Drake survives at least one attack from full health, but he bleeds from this.