RuneScape features a real-time combat system. Combat is an important aspect of the game, allowing players to retrieve items or gold dropped by dead creatures. Combat is also necessary to complete many quests. A combat level gives an indication of how powerful a player or NPC is in combat. For players, it is determined by applying a formula to the eight combat skills. Players engage in combat by clicking on the enemy they wish to attack. A player will automatically continue fighting until they kill their opponent, die, or leave the fight by running away, teleporting or logging out. Most of the game's weapons are medieval or fantastical in nature and feature different strengths and weaknesses. Players may also summon a familiar to assist with combat.

Combat is subdivided into three main categories: melee, magic and ranged. Melee attacks are close range with or without weapons,magic attacks focus on using runestones to cast spells, and ranged attacks use projectile weapons like arrows,darts or knives. These combat types make up the "Combat Triangle". Melee attacks are most effective against ranged opponents, ranged attacks are most effective against magic opponents and magic attacks are most effective against melee opponents. Unlike most games in the MMORPG genre, RuneScape gold does not require players to choose a character class nor are players bound to a specific category of combat. They may freely change between the three styles of combat at any time by switching weapons and armour. Players can even carry the weapons and armour of the three combat categories in their inventories and switch between or combine the styles. The advantages and disadvantages of the combat triangle apply to both NPCs and player opponents.

Players die when their hitpoints are reduced to zero. Lost hitpoints can be recovered by eating or drinking. Players can use potions and the "prayer" skill to boost their combat ability and defences. Players who die reappear at one of three respawn points with their hitpoints, and any other reduced skill levels, restored; however, they drop all but their three most valuable items. A special prayer allows the retention of one more item. There are situations in which all items will be lost upon death, or just one with the prayer. The items dropped form a gravestone, and they can be retrieved if the player can return to the gravestone before it dissipates. Players can purchase longer lasting gravestones and fellow players can repair or bless a gravestone to make it last longer. PVP combat can now only be performed in specific controlled mini games. Bounty Hunter gives players a chance to keep their opponent's items, Duel Arena offers limited staking, and some other PvP type games offer their own rewards (Fist of Guthix, Castle Wars, etc.)

Before 2008, Player Killers (pkers) were players that went to an area known as the Wilderness, to fight other players within a certain combat level range, hoping to gain their items. In RuneScape gold Classic, players could opt in to PvP in most areas outside of Lumbridge. Many player killers created "pures", which were min-max characters designed to have as low of a combat level as possible by heavily training some combat skills and not training other skills to achieve a desired advantage in the combat triangle. However, in December 2007 the Wilderness was radically changed to prevent players from transferring in-game items for real currency. New creatures called Revenants were added to maintain adverse pressure on players in the Wilderness, and PvP was restricted to specific mini games as mentioned above.