Claire first meets John Grey when she and Jamie are camping near Carryarrick, on their way to meet up with the rest of the Highland Army.

While scouting for his brother Harold, Duke of Pardloe's regiment, a sixteen-year-old John happens upon their Jacobite camp. He hears Claire's accent and immediately believes that she is a hostage. Seeing the infamous James Fraser only confirms his initial assumption.

Jamie quickly foils John's clumsy attempt to cut his throat. Jamie threatens to kill John in retribution, though he wants to interrogate him first.

When his initial interrogation attempts fail, Jamie takes advantage of John's chivalry by threatening to "rape" Claire, even going so far as to rip her gown open in illustration. A desperate Lord John agrees to tell Jamie what he knows in exchange for Claire's safety. After he's interrogated, John asks Jamie to assure him that Claire will be safe, at which point Jamie reveals that Claire is his wife.

Jamie ostensibly still plans to kill John, but an angry Claire argues that there's no evidence that John is a spy. Jamie, who was relying on Claire to come up with just such an argument, agrees to spare John's life. Claire binds John's broken arm before he departs, humiliated.

Years later, John and Jamie are reunited in Ardsmuir. Jamie thanks John for trying to protect Claire and tells him that Claire is dead.

Claire and John are reunited twenty years later on the Porpoise. Neither of them recognize one another. Claire, in the midst of battling a typhoid outbreak, is feeling hopeless and angry. John comforts "Mrs. Malcolm," and tells her he knows what it's like to feel responsible for men's lives.

A week later, Jamie and Claire are unexpectedly reunited with John. John is pleased to see "Mrs. Malcolm," but shocked when she introduces her husband Jamie.

Later that night, Claire sees Lord John Grey embracing Jamie tightly, and realizes at once that John has feelings for Jamie. She angrily confronts John, who admits his feelings for Jamie and tells her about William Ransom. Claire is even more taken aback when John reveals that he was the sixteen-year-old boy who tried to "rescue" her at Carryarrick.

John and Claire see each other again in October 1768, when John brings William to the Ridge. Claire is displeased to see him and is somewhat jealous of his relationship with Jamie. When John contracts the measles, Claire nurses him through the illness, giving them a chance to talk about their feelings. Both reveal that they are jealous of the other's relationship with Jamie. John tells Claire that his relationship with Isobel was affectionate but distant, and confesses he did not feel a significant amount of grief at her death. He also compliments Claire, and thanks her for saving his life. Claire softens toward him over the course of their time together, particularly after an incident with Gerhard Mueller.

In 1770, John Grey befriends Claire's pregnant daughter Brianna. Over the next few years, John sends Jamie and Claire multiple gifts, including the required items to make ether. In 1773, Lord John Grey sends one of his servants, Bobby Higgins, to be treated by Claire.

In June of 1777, Claire visits a Philadelphia shop in search of the ingredients for ether, but finds that Lord John has purchased the store's entire stock. Surprised, she rushes to the address given to her by the proprietor and reunites with Lord John.

Lord John is surprised but pleased to see her again, and reveals that he bought the ether in the hopes that Claire could use it to treat his nephew, Henry Grey. She and Denzell Hunter successfully perform surgery on Henry.

In April of 1778, John hears that the Eutrepe has sunk. Believing Jamie to be dead, he rushes to inform Claire. Both Claire and John are grief-stricken over Jamie's death. Only hours later, John encounters Captain Richardson, who tells him that he intends to arrest Claire for espionage.

John returns to the printshop at once and insists Claire marry him for protection. He tells Claire it's the last service he can perform for Jamie Fraser.

The two are married in John's home at Number 17 Chestnut Street. The day after their wedding, John gives Claire a large chest of medical equipment as a wedding present. Claire, remembering a similar anniversary gift Jamie had given to her a decade earlier, faints.

A week after her marriage to Lord John, she and John drunkenly sleep together. The following morning, both talk about Jamie and admit they are using each other to connect with Jamie's memory. John also talks of his sexual relationship with Isobel and his current relationship with his cook at his home in Virginia.

Though still mourning, Claire begins to settle into her life with Lord John, and develops a close relationship with her new step-son, William and niece Dottie. Claire asks Lord John if he believes she (and Brianna and Roger) are from the future, to which he says that he doesn't, but that he will behave for all appearances as though he does.

Approximately two months after their marriage, Jamie appears at Number 17 Chestnut Street. Both John and Claire are thrilled. However, things quickly go south when British soldiers arrive. Jamie is forced to leave with John as a fake hostage.

After leaving Philadelphia, John confesses that he slept with Claire, and angrily tells Jamie that he and Claire were both "fucking you." Furious, Jamie punches John in the eye. A group of continental soldiers arrive, and Jamie is forced to hand John over to them before making his way back to Philadelphia.

Meanwhile, Claire has come into contact with John's brother, Hal. He knows she is John's new wife and is asking questions about John's whereabouts. Claire is concerned that an investigation will lead to consequences for Jamie. Before she can formulate a plan, Hal suffers an asthma attack. Claire takes Hal back to the house for treatment, saving his life. However she continues to hide her knowledge of John's whereabouts and essentially holds Hal hostage.

Later, Claire and Jamie join the continental army. Outside of Philadelphia, they come across Lord John, masquerading as a continental soldier. Claire treats Lord John's dislocated eye with the help of her grandson and John's loyal new orderly, Germain Fraser.

After Claire is shot, John visits her and Jamie to ask after her recovery. He teases Claire and makes her laugh, which annoys Jamie. He offers the use of his home in Philadelphia in exchange for Jamie's help in finding William. Jamie turns down the offer, but agrees to help Hal and John find William.

A month later, Claire is among the attendees at John's niece Dottie's wedding, though they do not speak. After John leaves Philadelphia, he writes to Claire to again offer his home for use as her medical practice. Claire encounters Ezekiel Richardson, who tells her he was a spy for the continental forces, and had tricked John into marrying Claire in the hopes of using Claire for information about John and Hal.

When Claire takes Fanny Pocock to claim the body of her sister Jane Pocock, she runs into John, who has come for the same purpose. She tells John what Richardson said, and warns him that Richard knows that John is gay.