During the Jacobite Rising of 1745, Grey's brother Hal takes his regiment to Scotland, and sixteen-year-old John goes with him. In September 1745, while scouting for the British army, Grey comes across a band of Scots, led by notorious rebel Red Jamie Fraser. Grey notices an English lady among them and thinks that she is being held against her will, so he attacks Fraser, but is overpowered. Fraser then takes advantage of Grey's chivalry and forces him to reveal the location of his regiment by threatening the lady, who turns out to be Fraser's own wife, Claire.

Between 1755 and 1756, Grey is the governor of Ardsmuir Prison and befriends Jamie Fraser, who is one of the prisoners. Grey eventually falls in love with Jamie and sometimes thinks about Jamie's dead wife, usually with feelings of jealousy and mild dislike, mentally referring to her as "the woman."

Grey meets Claire for the second time in early 1767, during an outbreak of typhoid fever aboard the Porpoise, a ship carrying Grey—the new governor of Jamaica—to the West Indies. Claire uses the name Mrs. Malcolm and Grey doesn't recognize her. At the time, he respects Mrs. Malcolm's efforts to stop the spread of illness.

Several days later, Jamie and Claire attend Lord John's reception in Jamaica, and Grey is shocked to learn that Jamie's wife is still alive. Later in the evening, Claire witnesses Jamie and Grey embracing, and realizes that Grey has feelings for her husband. Grey explains to her how he and Jamie became friends, and that he is the stepfather of Jamie's illegitimate son William.

In October 1768, Lord John brings William to the Fraser's Ridge and contracts measles. While Jamie takes William for a trip to prevent the boy from contracting the illness, Claire treats Lord John. Initially, Claire is jealous of the easy conversation he makes with Jamie, a reminder of all the years John had Jamie and she did not, but she and John form something of a bond as Grey's illness runs its course over several days. Grey tells Claire that he has often wondered what Jamie had seen in her, and remarks that she has Jamie's courage.

In March 1770, Grey meets Brianna Fraser, Claire and Jamie's pregnant daughter, at River Run. They become friends and get conspicuously engaged to protect Brianna from other suitors. Grey tells Brianna that he has feelings of affection for her mother, and Brianna says that Claire considers Grey a good man and likes him.

Upon the Frasers' return in May, Claire is grateful to Lord John for looking after their daughter in their absence.

In September 1773, John sends Claire a gift of handcrafted glass globes and oil of vitriol for producing ether.

In July 1777, John writes a letter to Jamie in which he asks Claire to come to Philadelphia to perform a surgery on his wounded nephew Henry Grey. However, he is unaware that the Frasers have already left the Ridge.

In April 1778, Claire arrives in Philadelphia where she is to operate on her grandson. In order to make ether for the surgery, she requires oil of vitriol and learns that Lord John Grey purchased a quantity of it several months earlier. Claire pays Grey a visit and Grey reveals that he bought the vitriol for her, hoping that she would operate on his nephew. They strike a bargain.

Several days later, Lord John receives news that the ship supposedly carrying Jamie to America has sunk. Grey also encounters Captain Richardson who intends to arrest Claire for spying. Grey asks Claire to marry him in order to protect her, and she agrees. During their marriage, Claire and John become intimate, and there is mutual respect and kindness between them. One night, they are both very drunk, mourning Jamie, and have sex.

In mid-June 1778, Jamie arrives at Lord John's house, very much alive, making John's marriage to Claire invalid. Both John and Claire are overjoyed by Jamie's appearance, and quite relieved that they are no longer married to each other. Hours later, Grey is beaten up by Jamie for—among other things—sleeping with Claire. When Claire and John meet again after a few days, she takes care of his swollen eye.

On June 28, 1778, Claire is shot during the Battle of Monmouth, and John visits her a few days later.

In January 1779, Claire learns from Richardson that he manipulated Grey into marrying her, hoping that Claire would become his asset and spy on Lord John and his brother Hal. Richardson also makes it clear that he is aware of Lord John's homosexuality, and Claire warns Grey.