Diablo III incorporates the Havok physics engine and enables players to utilize the environment to help in their quest. For example, huge walls can be reduced to rubble to squash monsters by a direct hit. Even monsters use the environment (such as Ghouls scaling the walls to reach the player). Many more parts of what appear to be a seamless background environment are destructible. Some dilapidated areas will also collapse (with or without harming the player) automatically when the player gets too near or passes under part of a structure.

The UI, including character screen and inventory is functionally similar to its predecessor, besides the graphical upgrades and more details in expanding tabs, and will be very familiar to Diablo II players.

Some stats (and their UI bars) were removed, including Stamina (and therefore Walking). The experience bar is now at the bottom of the screen spanning across the UI panel. Some other stats were changed or added, but overall, remain similar to what they used to be.

Stat allocation is changed to Paragon system, allowing players to allocate excessive stats after reaching maximum level (60 or 70 with expansion), but before that, core stats are distributed automatically. Paragon levels continue to increase without limit after reaching maximum level, and are shared among all characters of same type on account.

Potions have lesser importance because of the introduction Health Globes, dropped by slain monsters. These replenish lost Life when picked up, and cannot be stored. Only one (endless) potion can be equipped, usable every 30 seconds, but potions may grant special effects in addition to restoring Life.

In co-operative play, loot is dropped for individual players (player cannot see what the others get). This was done to encourage trading between players in a group and reducing thievery. Co-operative play remains as the core of multiplayer, with a drop-in, drop-out feature so one can share their items (only available 2 hours after they drop, and only to players who were in the same party when item dropped). Between characters of same type on same account, gear may be transferred at any time.

Prior to patch 2.0, Auction House allowed players to trade their items for gold or real money.

Hardcore mode appears in Diablo III, with similar functionality to its prior incarnation. As of RoS, another choice during character creation is Season participation, which replaces the Ladder.

Players now can only learn 6 active skills (+3 or 4 passive), but can change those at any time for free. Skill Trees are gone, replaced with free choice almost without limits (some skills are limited to one per category). To compensate, skills can be upgraded with skill runes to change their functionality, and gear offers new stats, which greatly improve functionality of skills (such as reducing cooldowns and resource costs, increasing their damage, etc) instead of plainly increasing skill levels. Sets also offer unique bonuses instead of simply increasing stats. Skill Points are also gone, players always have access to a number of skills based on their character level.

There are four slots for keyboard activated skills, associated with the 1-4 number keys, and two are the mouse skills (LMB and RMB).

Buffs and debuffs are now displayed on the UI. As of patch 2.4, they are grouped and incorporated into skill icons for better visualization.

There is now a mini-map displayed on the top of the right hand side of the screen, replacing the automap. A detailed map can be viewed at any time with M key.

Action Combat feature, originally exclusive to consoles, was implemented on PC in 2.4.

The game is designed so that ideally, there is a change of art assets and monsters every fifteen minutes when playing the game.