In 1516, Okimoto died. Okimoto's son Kōmatsumaru succeeded to the leadership of the clan, and Motonari became his overseer. Kōmatsumaru died eight years later in 1523, and Motonari succeeded him.
Sandwiched between the powerful Amago and Ōuchi clans, Motonari led the clan by carefully balancing actions and diplomacy. Eventually, Motonari succeeded in defeating both and controlled the entire Chūgoku area. In his late years, he crushed the Ōtomo clan of Bungo province.
He had three sons, Mōri Takamoto, Kikkawa Motoharu, and Kobayakawa Takakage, whom he encouraged to work together for the benefit of the Mōri clan. In one instance, he is said to have handed each of his sons an arrow and asked each snap it. After each snapped his arrow, Motonari produced three arrows and asked his sons to snap all three at once. When they were unable to do so (according to a legend still taught today), Motonari explained that one arrow could be broken easily, but three arrows held together could not.
His eldest son, Mōri Takamoto died of a sudden disease, some say poisoning, while enroute to attack the Amago clan. Saddened and angered by his death, Motonari ordered all those responsible to be punished.
In all, Motonari had nine sons and two daughters—four children (including Takamoto, Motoharu, and Takakage) with his wife, Myōkyū (name while alive is unknown, in NHK's TV drama Mōri Motonari she is introduced as Mii-no-kata), three with a woman from the Nomi clan, and four with a woman from the Miyoshi clan.