Green Little is a Quaker farmer with a conflicted passion for drinking and fighting. Thanks to a bond with an unlikely friend confined to servitude, he has somehow survived. As Green, his wife, and their children try to begin a new life, he must leave his friend behind. As the years pass, his family becomes larger, while the possibility of a Civil War grows greater, Green is about to discover that fate will play an even bigger part in his life than he ever imagined.

Meanwhile, Old Jeb is battling just to survive in the pre-war South. In an effort to protect his wife and five children from constant threats, he reluctantly leaves his beloved family behind and escapes to Indiana to establish a trade, hoping his wife and children can soon follow. When he joins the Union Army in an effort to find his family again, he has no idea that Green's has joined up to fight for the Confederates. As the two men arrive at the battle of Gettysburg via separate roads, their destinies await.

West of Cayuga shares the historical tale of two friends--one white and one black--as they embark on separate journeys of survival during the Civil War era.