Washington DC 1844: When his mother is found drowned in the Potomac, 15-year-old Samuel Evans is devastated and falls gravely ill, saved by an experimental drug given to him by the gruff Dr. James Pyper who developed it from an Amazonian plant. The drug makes Samuel so sensitive to his environment that he can communicate with animals. He sets out to prove his mother didn't commit suicide, helped by encounters with numerous animals.

The doctor's childless wife, Martha, convinces her husband to adopt Samuel. He discovers that their house is a stop on the Underground Railroad and that Martha helps runaway slaves.

While investigating his mother's murder, Samuel's life is threatened, he falls in love, he dispatches a bee hive to punish the man he suspects, and tragedy ensues. He is kicked out of the Pypers' house, with nowhere to go. During this painful time, he uncovers lies and betrayal from people he trusts before learning the truth about his parents.

The Orphan is set against the backdrop of slavery and the 1844 presidential election that determined whether Texas would enter the union as a slave state.