Spice and Wolf's story revolves around Kraft Lawrence, a 25-year-old traveling merchant who peddles various goods from town to town to make a living in a stylized historical setting with European influences.[6] 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 girl 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.

Kraft Lawrence (クラフト・ロレンス Kurafuto Rorensu?)
Voiced by: Jun Fukuyama (Japanese), J. Michael Tatum (English)
Kraft Lawrence, who chiefly goes by his surname, is a 25-year-old traveling merchant who goes from town to town buying and selling various things in order to make a living. When he was twelve, he became an apprentice to a merchant relative, and set out on his own at eighteen. His goal in life is to gather enough money to start his own shop, and he has already been traveling for seven years while gaining experience in the trade. He meets Holo one night and eventually agrees to her traveling with him. She helps him by providing her wisdom which helps to increase his profits and get him out of jams. 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. He shows his affection through his actions, such as when Holo gets captured by the Church and Lawrence completely panics. Lawrence mentions he has been attacked by wolves eight times.

Holo[7][8][9][N 1] (ホロ Horo?)
Voiced by: Ami Koshimizu (Japanese), Brina Palencia (English)
Holo is a wolf harvest deity originally from a place in the north known as Yoitsu. She made a promise with men from a town called Pasloe that she would ensure the town would have good wheat harvests year after year. However, as time went on, the townspeople slowly started to forsake Holo and did not rely on her as they once did. As such, Holo escapes from town in Lawrence's wagon and started traveling with him to see how much the world has changed since she has been in Pasloe. Holo has chosen the form of a girl younger than Lawrence, though she still retains her large white-tipped wolf tail, and ears. At times she can produce an ear-shattering howl. Her true form is that of a very large wolf which many people revered and feared.

She refers to herself as the "Holo The Wise Wolf" (ヨイツの賢狼 Yoitsu no Kenrō?, Wise Wolf of Yoitsu). She is typically very haughty and self-sufficient, though due to her isolation for hundreds of years in Pasloe, she gradually feels very lonely, and sometimes shows a more fragile side of herself. She relies on Lawrence for company as she fears loneliness, which is something that Lawrence is very aware of and tries to comfort her in his own way. 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. She has a peculiar way of speaking, modeled after that of the oiran high-class courtesans.[11] She is fond of delicious food and alcohol, but especially loves apples. She takes pride in her tail and takes special care of it, constantly combing and maintaining it.

Yarei (ヤレイ?)
Yarei is a light novel and manga-only character. He is a farmer of Pasloe and has a long history of facilitating deals with Lawrence. On the day Lawrence passes through Pasloe Yarei "catches the wolf" in the town's yearly harvest festival. Instead Holo escapes to a larger sheaf of wheat in Lawrence's wagon. When they meet again in Pazzio Yarei certainly knows of the existence of Holo, but looking her in the eye he avows his faith in modern methods and seeks to turn her over to the Church for burning.

Chloe (クロエ Kuroe?)
Voiced by: Kaori Nazuka (Japanese), Jamie Marchi (English)
Chloe is an anime-original character. She is a villager of Pasloe and has known Lawrence for a long time. In fact, Lawrence taught her how to be a merchant. She had a slight interest in Lawrence, but tries to push the feelings away. Despite still not knowing how she should feel about him, she respects him as her teacher and a good friend. They later break off their friendship when Chloe allies with the Church to capture Holo and Lawrence. She substitutes for Yarei in the anime.

Norah Arendt (ノーラ・アレント Nōra Arento?)
Voiced by: Mai Nakahara (Japanese), Leah Clark (English)
Norah makes her first appearance in volume two of the novels. She is a skilled shepherdess from a church-town named Ruvinheigen. Her companion in this profession is a well-trained sheep dog named Enek (Enekk in the anime). Lawrence entrusts her with a task after they meet.

Fermi Amati (フェルミ・アマーティ Ferumi Amāti?)
Voiced by: Saeko Chiba (Japanese), Ryan Reynolds (English)
Amati, who just like Lawrence mainly goes by his surname for business, makes his first appearance in volume three of the novels. He is a young man who works as a fish broker. He has a crush on Holo, and proposes to her. Due to Holo's good acting, he believes her to be gentle, kind and a soft spoken, polite young lady.

Dian "Diana" Rubens (ディアン・ルーベンス Dian Rūbensu?)
Voiced by: Akeno Watanabe (Japanese), Colleen Clinkenbeard (English)
Dian, who first appears in volume three of the novels, is a chronicler, living in Kumersun's walled ghetto with other "suspect" persons such as alchemists. She loves to collect pagan tales and beliefs and has written them into a set of books. Lawrence has come to her to ask for information about Holo's birthplace Yoitsu. Since Dian sounds like a masculine name, she asks Lawrence to call her Diana. According to Holo, Dian is not human, but a bird even bigger than Lawrence. She fell in love with a traveling priest and spent a few years helping him build a church, but left because he noticed that she never seemed to grow old and became suspicious.

Mark Cole (マルク・コール Maruku Kōru?)
Voiced by: Rikiya Koyama (Japanese), Ian Sinclair (English)
Mark Cole is a town merchant, a wheat seller in Kumersun. He and his apprentice, Eu Landt, assist Lawrence in his contest with Amati, and provide dialog counterpoint to Lawrence and Holo.