Brother's Keeper is a story about two brothers of the same mother but different fathers, "Sam" Kiu Tin-seng (Ruco Chan) and Lo Wai-son (Edwin Siu). Sam was born in Hong Kong, the son of Chow Yuk-mui (Louise Lee) and Kiu Sum (Lee Kwok Lun). Due to Kiu Sum refusing to marry Chow Yuk-mui, Yuk-mui decided to take Sam to Foshan, China to start anew. In Foshan, Yuk-mui got married with Lo Fu-shing (Lau Kong) and gave birth to Sam a few years afterwards.
Not long after, the family of four decided to cross the border to start a new life in Hong Kong. The family of four eventually got separated with Sam ending up in Hong Kong, while Yuk-mui, Fu-shing, and Son ending up in Macau.
The two brothers lived very different lives in the course of the next 20 years. The very hardworking and ambitious Sam managed to graduate from college and became a police officer like his biological father, Kiu Sum. He has a girlfriend named Rachel Cheuk (Linda Chung) whom he is willing to do anything to fulfill her dreams of opening a fashion store. In order to achieve his goal, he seduces Fabio (Ankie Beilke) and uses her in the process. In addition, Sam also has an ambiguous relationship with a triad member named Keung Yung (Louis Cheung) who later caused Sam to end up in jail.
Son, who is very simple-minded, only wants to live a peaceful and comfortable life in Macau. He is good friends with Yiu Man-ying (Krystal Tin) and Lung Fei (Louis Yuen). In order to avoid his abusive father (Fu-shing), Fu-shing works with his mother (Yuk-mui) at a restaurant. The lives of the two brothers, Sam and Son began to change after they meet up again. The two brothers in the series will go from 20 to 50 years old. This also shows the phrase "rags to riches" as Edwin Siu becomes a rich businessowner from a poor young boy.