Scene 1
The play opens in an unidentified street of London around the year 1480. Richard of Gloucester, the chief protagonist of the play, is the brother of King Edward IV and of George, the Duke of Clarence, most often called "Clarence" in the play. Alone on stage, the figure of Richard, misshapen with a hunchback from his premature birth, first tells us that the recent civil wars between the houses of Lancaster and York are now over, that Richard's side (York) is victorious, but that he himself is discontent. Being "ill-formed" by nature, Richard is not suited to peaceful times when romance holds sway. That being so, he is "determined to prove a villain." He has laid a plot against his own brother, Clarence, inciting his other brother (the recently crowned King Edward) to arrest the innocent Clarence by pouring "drunken prophecies, libels, and dreams" into the King's ear. After this extensive opening soliloquy is done, Clarence appears in the custody of the king's guards, headed for the prison Tower of London. Richard pretends to sympathize with Clarence, blaming King Edward's wife (Queen Elizabeth, born the Lady Grey) for Clarence's plight. Clarence is led away, and the recently jailed Lord Hastings arrives with news that the new King is gravely ill. When he departs, Richard has another opportunity to disclose his plans for his brother, saying that he will engineer Clarence's execution because his brother is an obstacle to his own regal ambitions. Incredibly, he also reveals that he plans to marry the Lady Anne, whose husband (Edward, Prince of Wales) he helped to murder at the end of Henry VI: Part III.

Scene 2
In another London street, we see the Lady Anne attending the funeral of Henry VI, her former father-in-law, a fallen monarch whom Richard of Gloucester also had a hand in killing. Richard then enters, and though he denies any involvement in the deaths of her husband and her father-in-law, Lady Anne calls him a "black magician" and a "hedgehog." For his part, Richard speaks of his desire to visit Lady Anne's bedchamber and eventually marry the woman he has made into a widow. At this perverse suggestion, she spits in his face while calling him a "foul toad." Claiming that any involvement in the murder of Anne's husband was motivated by his love for her beauty, Richard hands Lady Anne a dagger and opens his breast to its point. Anne refuses to be his executioner, and when Richard assumes a penitent stance, she agrees to accept a ring from him. After Lady Anne exits, Richard exalts in his own powers, asking the rhetorical question: "Was ever woman in this humor won?"

Scene 3
The scene now shifts to the royal palace in London. Queen Elizabeth speaks with her relatives and expresses the fear that when the current monarch (Edward IV) dies, Richard of Gloucester will be named protector over his two sons, providing the uncle with a means to take the throne himself. She knows that this will also bode ill for her entire family, including her brother (the Lord Rivers) and her own sons (the Lords Dorset and Grey). One of the villain Richard's allies, Buckingham, appears; and then Richard himself enters. Richard professes his innocence on all counts and argues with the old Queen Elizabeth. Accompanied by Hastings, Richard blames the Queen and her family for Hastings false imprisonment. Queen Margaret, the wife of the deceased Henry VI, enters; and she, too, expresses her hatred toward Richard, warning Buckingham against him. When all of these characters except Richard himself depart, the villain reveals his plans to have Clarence killed in the Tower by two murderers. When they arrive, Richard tells the felons not to listen to Clarence's pleas for mercy.

Scene 4
The scene shifts to Clarence's prison cell within the Tower of London. Clarence tells his jailer that he has had horrible dreams that seem to say that his real enemy is not the Queen but his own brother, Richard of Gloucester. Richard's two henchmen appear. Against Richard's instructions, they speak with Clarence and disclose that Richard, in fact, hates Clarence. He implores them to relent. One of the murderers feels pangs of conscience, but the other says that to relent now would be "cowardly and womanish." He then stabs Clarence to death.