In Juban, Tokyo, a middle-school student named Usagi Tsukino befriends Luna, a talking black cat who gives her a magical brooch enabling her to transform into Sailor Moon: a soldier destined to save Earth from the forces of evil. Luna and Usagi assemble a team of fellow Sailor Soldiers to find their princess and the Silver Crystal. They encounter the studious Ami Mizuno, who awakens as Sailor Mercury; Rei Hino, a local Shinto shrine maiden who awakens as Sailor Mars; Makoto Kino, a tall and strong transfer student who awakens as Sailor Jupiter; and Minako Aino, a young aspiring idol who had awakened as Sailor Venus a few months prior, accompanied by her talking feline companion Artemis. Additionally, they befriend Mamoru Chiba, a high-school student who assists them on occasion as Tuxedo Mask.
In the first arc, the group battles the Dark Kingdom. Led by Queen Beryl, a team of generals—the Four Kings of Heaven (四天王, Shiten'ō, lit. "Four Heavenly Kings")—attempt to find the Silver Crystal and free an imprisoned, evil entity called Queen Metaria. Usagi and her team discover that in their previous lives they were members of the ancient Moon Kingdom in a period of time called the Silver Millennium. The Dark Kingdom waged war against them, resulting in the destruction of the Moon Kingdom. Its ruler Queen Serenity later sent her daughter Princess Serenity, her protectors the Sailor Soldiers, their feline advisers Luna and Artemis, and the princess' true love Prince Endymion into the future to be reborn through the power of the Silver Crystal. The team recognizes Usagi as the reincarnated Serenity and Mamoru as Endymion. The Soldiers kill the Four Kings, who turn out to have been Endymion's guardians who defected in their past lives. In a final confrontation with the Dark Kingdom, Minako kills Queen Beryl; she and the other Soldiers then sacrifice their lives in an attempt to destroy Queen Metaria. Using the Silver Crystal, Usagi defeats Metaria and resurrects her friends.
At the beginning of the second arc, Usagi and Mamoru's daughter Chibiusa arrives from the future to find the Silver Crystal. As a result, the Soldiers encounter Wiseman and his Black Moon Clan, who are pursuing her. Chibiusa takes the Soldiers to the future city Crystal Tokyo, where her parents rule as Neo-Queen Serenity and King Endymion. During their journey, they meet Sailor Pluto, guardian of the Time-Space Door. Pluto stops the Clan's ruler Prince Demand from destroying the spacetime continuum, leading to her death. Chibiusa later awakens as a Soldier—Sailor Chibi Moon and helps Usagi kill Wiseman's true form, Death Phantom.
The third arc revolves around a group of lifeforms called the Death Busters, created by Professor Soichi Tomoe, who seek to transport the entity Pharaoh 90 to Earth to merge with the planet. Tomoe's daughter, Hotaru, is possessed by the entity Mistress 9, who must open the dimensional gateway through which Pharaoh 90 must travel. Auto-racer Haruka Tenoh and violinist Michiru Kaioh appear as Sailor Uranus and Sailor Neptune, who guard the outer rim of the Solar System from external threats. Physics student Setsuna Meioh, Sailor Pluto's reincarnation, joins the protagonists. Usagi obtains the Holy Grail, transforms into Super Sailor Moon, and attempts to use the power of the Grail and the Silver Crystal to destroy Pharaoh 90. This causes Hotaru to awaken as Sailor Saturn, whom Haruka, Michiru, and Setsuna initially perceive as a threat. As the harbinger of death, Hotaru uses her power of destruction to sever Pharaoh 90 from the Earth and instructs Setsuna to use her power over time-space to close the dimensional gateway.
In the fourth arc, Usagi and her friends enter high school and fight against the Dead Moon Circus, led by Queen Nehelenia, the self-proclaimed "rightful ruler" of both Silver Millennium and Earth. Nehelenia invades Elysion, which hosts the Earth's Golden Kingdom, capturing its High Priest Helios and instructing her followers to steal the Silver Crystal. As Prince Endymion, Mamoru is revealed to be the owner of the Golden Crystal, the sacred stone of the Golden Kingdom. Mamoru and the Soldiers combine their powers with those of the Holy Grail, enabling Usagi to transform into Eternal Sailor Moon and kill Nehelenia. Four of Nehelenia's henchmen, the Amazoness Quartet, are revealed to be Sailor Soldiers called the Sailor Quartet, who are destined to become Chibiusa's guardians in the future; they had been awakened prematurely and corrupted by Nehelenia.
In the fifth and final arc, Usagi and her friends are drawn into a battle against Shadow Galactica, a group of false Sailor Soldiers. Their leader, Sailor Galaxia, plans to steal the Sailor Crystals of true Soldiers to take over the galaxy and kill an evil lifeform known as Chaos. When Galaxia kills Mamoru and most of the Sailor Soldiers, she steals their Sailor Crystals. Usagi travels to the Galaxy Cauldron to defeat Galaxia and revive her teammates. Joining Usagi are the Sailor Starlights who come from the planet Kinmoku, their ruler Princess Kakyuu and the infant Sailor Chibichibi, who comes from the distant future. Later, Chibiusa and the Sailor Quartet join Usagi and company. After numerous battles and the death of Galaxia, Sailor Chibichibi reveals her true form as Sailor Cosmos. After defeating Chaos with the Silver Crystal, Usagi revives Mamoru and the Sailor Soldiers, before returning to Earth. The series ends with Usagi and Mamoru's wedding six years later.