1843. US Senator William Tadlock (played by Kirk Douglas) is following the Oregon Trail with his family from Missouri, and to help him get there safely - is Dick Summers (played by Robert Mitchum), a scout. His son and help are also accompanying Tadlock. Although Summers advises William not to go ‘especially if you’ve never been there’- the Senator thinks otherwise, he tells Dick he knows that he is grieving for his dead Indian wife, he asks William to leave. Tadlock, also a widower, thinks that the scout’s grief has corrupted his guts.
Meanwhile, the others accompanying William on the trail are a peasant couple from Pennsylvania, Lije Evans and Rebecca (played by Richard Widmark, Lola Albright). Becky isn’t happy about the move, though. They have a sixteen year old son Brownie (Michael McGreevy), who is funny and brimming with the joie de vivre of youth - impressing young Mercy McBee with a red fox kitten. Others include a newlywed couple, the Fairmand and the McBee family.
That day, when Summers suggests they camp for the night, William notices another wagon trail, and insists they keep moving. The trail races into the creek, and everyone puts their back into making it first. A fist fight ensues when Tadlock tells the rival trail members that his trail will cross first - considering it might rain that night. Summers breaks up the fight and points out that Tadlock knew all along that the rivals weren’t travelers, but part of a cattle train - offended, William asks him not to gall him with his ‘truthful opinions’ - he is paid after all, to only point the way. (Cattle may drown if the rain-filled river were to overflow).
Meanwhile they welcome a stowaway - Brother Weatherbee - slave to the Holy Ghost, who has only the spirit of Christ and the shirt on his back in lieu of supplies! The others are happy with the decision, for a preacher ‘will overcome the calamities of human nature - such as weddings, babies…’ ‘…funerals…’ Dick Summers volunteers to look after him, much to Tadlock’s chagrin and consternation.
The wagon trail’s first tragedy strikes, when Tadlock in his quest for speed, forces the oldest member of the group to cross the creek - he loses his life by drowning. Things get worse when William holds the old man responsible for his end, to which Lije vehemently puts up a denial, saying it was speed that killed him. The Senator even asks McBee to hurry with the burial and not bother with a Christian funeral - a waste of time. His apathy shocks the trail. But William proves his point that greed was responsible for the tragedy - the man had a heavy belt with money tied to his waist, which prevented him from coming to the surface. He asks if anyone cares to have a share of ‘dead man’s money’ - he flings the belt back into the creek.
The Prairie gives way to the inhospitable and hot desert terrain, but the love lorn lads sing ballads for Mercy McBee - whilst Johnnie and Amanda Mack (played by Michael Witney, Katherine Justice) unsuccessfully try consummating their marriage in a crowded train. This distresses Amanda, who does not want to get pregnant on the train - and frustrates her young husband. Whilst the members cast their cares to the wind and enjoy a morning of revelry, Tadlock shows Rebecca Evans the map of a city – yet to be built in Oregon. He tells her he might’ve been president, save for the fact that he fell in love with a woman, married her, but she died. William goes onto tell her that none in the present company would understand her vision - save for Becky. Disturbed by the depth of his emotions, Rebecca leaves his tent in a hurry.
Elsewhere, young Brownie has wandered far from the train, he stands on an outcrop - carving his name and Mercy’s - when unbeknownst to him - Sioux Indians hiding beneath the rock - take him captive. Dick Summers comes to his rescue - speaking to the men in their native tongue. The Sioux escort them back to the train. Summers offers them supplies - they ask for whiskey, instead!
That night, while the Sioux are in a state of drunken partying, Mercy and Mack find an opportunity to bond- he eventually seeks solace in Mercy’s willing arms - who tells him she does not regret what has happened. He asks her to return to her parents. Hearing a rustle in the bushes, he looks up to see a wolf - without preamble, Mack shoots it down. When he inspects to see what it is - he runs.
Meanwhile, Summers and Tadlock discover that the wolf was actually a little boy - the Chief’s son. They have no clue who is responsible. The next day, Dick and Lije distract the Sioux, leading them on a wild goose chase - so that the train can move ahead smoothly, through a herd of bison. Mercy, deeply in love with Mack, is saddened by his refusal to reciprocate the same for her.
The Sioux come again to the camp - this time, bearing the dead child on horseback - hungry for the blood of the murder. Tadlock tells him that he will fulfill their wishes, if they let the train go free. William tells the people present that if the perpetrator does not give himself up - Brownie Evans will be hanged, for it was he who brought this calamity today. However, he asks all the men who own shotguns - to step up and own up. Just then Johnnie Mack confesses - his wife lies on his behalf, saying he was with her all that night. But Mack sticks to his story - and is hung. A grief stricken Mercy flings herself off of her wagon, Brownie saves her, and he asks her to marry him - she refuses at first, because she doesn’t love him, however agrees since she is pregnant.
Tadlock and Summers labor on, and one day, he loses his son in a mad stampede. He buries him in the wilderness, as wagons drive over the burial mound, so that wolves and Indians find no trace of the grave. So sad and distraught is the man, that he asks his slave to whip him. The wagon train finally reaches the periphery of Fort Hall, Oregon, where other pioneers welcome them, they stop for the night - and Brownie and Mercy get married. One last hurdle is the soldiers who try and stall them at the Fort, bribing them with money and animals - William tells them to let them go, since a woman has been infected with small pox. The colonel orders them out.
Winter falls upon them, and the travelers face many hardships. Lije Evans turns on Tadlock, wanting charge of the train. When William tries shooting Evans, the mob falls upon him - as Becky shouts out to them that he ought to be hanged like Mack. Tadlock jeers at them, saying they lack the courage to do so - meanwhile, Becky shares Tadlock’s vision, when the train hits a ravine, as Evans contemplates turning back. Summers tells them that if they cross the gorge - they’ll be closer to Oregon. And so, they devise a pulley to lower people down the gorge, with success; however, as Tadlock rappels down - Becky cuts away the rope - he falls to his death: Captain William Tadlock, who led the Oregon Liberty Company.