Sam Manson is one of Danny's best friends. She is a deadpan goth who doubles as an environmentally concerned "ultra-recyclo-vegetarian". Her parents are extremely wealthy and have inherited from their famous inventor ancestor, who invented "the machine that twirls the cellophane around the toothpicks", though she briefly kept it a secret from her friends to avoid "fake friendships". She and her parents often clash due to their differences.

Sam is often the most pragmatic of the group, but she can be bossy at times and determined to stand up for what she believes in, particularly when environmental causes are involved. But she is also very warm and caring and is always there for Danny no matter what. She was the one who urged Danny to explore the then-under-construction Fenton Portal, resulting in the accident that gave Danny his ghost powers. Her favorite ice cream has black icing and gummy bats. She has a crush on Danny that lasts throughout the majority of the series, and she eventually becomes his girlfriend.

Sam has also been unintentionally responsible in the development of ghosts. In the episode "Urban Jungle", Undergrowth brainwashes Sam into becoming his queen and "personal care taker of everything green". In the episode "Memory Blank", Sam causes Danny to lose his powers out of anger because of the wish-granting ghost Desiree and also brings to life three ghosts from a horror movie, Femalien, Terminatra, and Nightmerica.