Spice and Wolf is the story that revolves around Kraft Lawrence, a 25-year-old traveling merchant who peddles various goods from town to town to make a living. His main goal in life is to gather enough money to start his own shop, and he already has been traveling for seven years while gaining experience in the trade. One night when stopped at the town of Pasloe, he finds in his wagon a pagan wolf-deity named Holo who is over 600 years old. She appears to be a 15-year-old girl, except for a wolf's tail and ears. She introduces herself as the town's goddess of harvest, who has kept it blessed with good harvests of wheat for many years. Despite her responsibility to watch over the town, she wants to go back to her homeland in the north called Yoitsu; she believes the people have already forsaken her and that she has kept her promise to maintain the good harvests. Holo wants also to travel to see how the world has changed while she has remained in one place for years. She manages to bargain her way out of the village by making a deal with Lawrence to take her with him. As they travel, her wisdom helps increase his profits, but at the same time, her true nature draws unwanted attention from the Church.
As the series progresses, both Lawrence and Holo demonstrate a growing affection toward each other. Although Lawrence rarely shows different facial expressions, he truly cares for Holo. Holo is also very aware of the different time spans that she and Lawrence have, as a human lifespan is like a blink of an eye for her kind. Holo is quite scared of that fact, but hides it with jokes. Although she jokes about her affections for Lawrence at first, she slowly but surely falls in love with him. That bond is soon tested when the two arrived in the town of Kumerson, where a young merchant named Fermi Amati takes in interest in Holo. One night in front of the Merchant Guild, Amati challenges Lawrence, proclaiming he will pay for Holo's falsified debt of 1,000 silver coins and then propose to her, certain that she will leave Lawrence.
Lawrence researches Amati, discovering that his plan to pay back the debt relies on the sale of pyrite. Lawrence participates in the pyrite market, selling small quantities several times to combat the rapidly rising prices, but to no avail. Lawrence all but gives up before he is spurred on by a young apprentice, Lant. When Lawrence goes to sell his remaining pyrite, Holo also sells a large bag purchased from Dianna Rubens, an alchemist, revealing that she was attempting to help Lawrence from the beginning. The market quickly turns to selling, dropping the price of pyrite and causing Amati huge losses. He fails to fulfill his portion of his challenge to Lawrence and gives up his marriage proposal to Holo as a result.
At the end of the series, Lawrence almost loses Holo in a deal that sounded good until a coup d'état happened, leaving them surrounded by a rebellion. Eve Bolan, a merchant from the port town of Renos made a contract with Lawrence which he soon wants out of in order to get Holo back. Eve threatens to murder him, since he discovered Eve had a cunning plan involving the Church to earn a huge amount of money. Eve knocks him out, but leaves him a deed to an inn, which he then uses to buy back Holo. In the face of Holo's apparent fury, Lawrence declares his decision to forgo his dream and keep traveling with Holo as well as stating his affection for her. They then head to the docks together as they prepare leave the town.