The story concerns Paul Dombey, the wealthy owner of the shipping company of the book's title, whose dream is to have a son to continue his business. The book begins when his son is born, and Dombey's wife dies shortly after giving birth. Following the advice of Mrs Louisa Chick, his sister, Dombey employs a wet nurse named Mrs Richards (Toodle). Dombey already has a six year-old daughter Florence but, bitter at her not having been the desired boy, he neglects her continually. One day, Mrs Richards, Florence and her maid, Susan Nipper, secretly pay a visit to Mrs Richard's house in Staggs's Gardens so that Mrs Richards can see her children. During this trip, Florence becomes separated from them and is kidnapped for a short time by Good Mrs Brown, before being returned to the streets. She makes her way to Dombey and Son's offices in the City and there is found and brought home by Walter Gay, an employee of Mr Dombey, who first introduces her to his uncle, the navigation instrument maker Solomon Gills, at his shop the Wooden Midshipman.
The child, named Paul after his father, is a weak and sickly child, who does not socialise normally with others; adults call him "old fashioned". He is intensely fond of his sister Florence, who is deliberately neglected by her father as irrelevant and a distraction. He is sent to the seaside at Brighton for his health, where he and Florence lodge with the ancient and acidic Mrs Pipchin. Finding his health beginning to improve there, Mr Dombey keeps him at Brighton and has him educated there at Dr and Mrs Blimber's school, where he and the other boys undergo both an intense and arduous education under the tutelage of Mr Feeder, B.A. and Cornelia Blimber. It is here that Paul is befriended by a fellow pupil, the amiable but weak-minded Mr Toots.
Here, Paul's health declines even further in this 'great hothouse' and he finally dies, still only six years old. Dombey pushes his daughter away from him after the death of his son, while she futilely tries to earn his love. In the meantime, young Walter sent off to fill a junior position in the firm's counting house at Barbados through the manipulations of Mr Dombey's confidential manager, Mr James Carker, 'with his white teeth', who sees him as a potential rival, through his association with Florence. His boat is reported lost and he is presumed drowned. Walter's uncle leaves to go in search of Walter, leaving his great friend Captain Edward Cuttle in charge of the Midshipman. Meanwhile, Florence is now left alone with few friends to keep her company.
Dombey goes to Leamington Spa with a new friend, Major Joseph B. Bagstock. The Major deliberately sets out to befriend Dombey to spite his neighbour in Princess's Place, Miss Tox, who has turned cold towards him owing to her hopes – through her close friendship with Mrs Chick – of marrying Mr Dombey. At the spa, Dombey is introduced via the Major to Mrs Skewton and her widowed daughter, Mrs Edith Granger. Mr Dombey, on the lookout for a new wife since his son's death, considers Edith a suitable match due to her accomplishments and family connections; he is encouraged by both the Major and the avaricious mother, but obviously feels no affection for her. After they return to London, Dombey remarries, effectively 'buying' the beautiful but haughty Edith as she and her mother are in a poor financial state. The marriage is loveless; his wife despises Dombey for his overbearing pride and herself for being shallow and worthless. Her love for Florence initially prevents her from leaving, but finally she conspires with Mr Carker to ruin Dombey's public image by running away together to Dijon. They do so after her final argument with Dombey in which he once again attempts to subdue her to his will. When he discovers that she has left him, he blames Florence for siding with her stepmother, striking her on the breast in his anger, and she is forced to run away from home. Highly distraught, she finally makes her way to The Midshipman where she lodges with Captain Cuttle as he attempts to restore her to health. They are visited frequently by Mr Toots and his prizefighter companion, the Chicken, since Mr Toots has been desperately in love with Florence since their time together in Brighton.
Dombey sets out to find his wife. He is helped by Mrs Brown and her daughter, Alice, who, as it turns out, was a former lover of Mr Carker. After being transported as a convict for criminal activities, which Mr. Carker had involved her in, she is seeking her revenge against him now that she has returned to England. Going to Mrs Brown's house, Dombey overhears the conversation between Rob the Grinder – who is in the employment of Mr Carker – and the old woman as to the couple's whereabouts and sets off in pursuit. In the meantime, in Dijon, Mrs Dombey informs Carker that she sees him in no better a light than she sees Dombey, that she will not stay with him and she flees their apartment. Distraught, with both his financial and personal hopes lost, Carker flees from his former employer's pursuit. He seeks refuge back in England, but being greatly overwrought, accidentally falls under a train and is killed.
After Carker's death, it is discovered that he had been running the firm far beyond its means. This information is gleaned by Carker's brother and sister, John and Harriet, from Mr Morfin, the assistant manager at Dombey and Son, who sets out to help John Carker. He often overheard the conversations between the two brothers in which James, the younger, often abused John, the older, who was just a lowly clerk and who is sacked by Dombey because of his filial relationship to the former manager. As his nearest relations, John and Harriet inherit all Carker's ill-gotten gains, to which they feel they have no right. Consequently, they surreptitiously give the proceeds to Mr Dombey, through Mr Morphin, who is instructed to let Dombey believe that they are merely something forgotten from the general wreck of his fortunes. Meanwhile, back at the Midshipman, Walter reappears, having been saved by a passing ship after floating adrift with two other sailors on some wreckage. After some time, he and Florence are finally reunited – not as 'brother' and 'sister' but as lovers, and they marry prior to sailing for China on Walter's new ship. This is also the time when Sol Gills returns to the Midshipman. As he relates to his friends, he received news whilst in Barbados that a homeward-bound China trader had picked up Walter and so had returned to England immediately. He said he had sent letters whilst in the Caribbean to his friend Ned Cuttle c/o Mrs MacStinger at Cuttle's former lodgings, and the bemused Captain recounts how he fled the place, thus never receiving them.
Florence and Walter depart and Sol Gills is entrusted with a letter, written by Walter to her father, pleading for him to be reconciled towards them both. A year passes and Alice Brown has slowly been dying despite the tender care of Harriet Carker. One night Alice's mother reveals that Alice herself is the illegitimate cousin of Edith Dombey (which accounts for their similarity in appearance when they both meet). In a chapter entitled 'Retribution', Dombey and Son goes bankrupt. Dombey retires to two rooms in his house and all its contents are put up for sale. Mrs Pipchin, for some time the housekeeper, dismisses all the servants and she herself returns to Brighton, to be replaced by Mrs Richards. Dombey spends his days sunk in gloom, seeing no-one and thinking only of his daughter:
He thought of her as she had been that night when he and his bride came home. He thought of her as she had been in all the home events of the abandoned house. He thought, now, that of all around him, she alone had never changed. His boy had faded into dust, his proud wife had sunk into a polluted creature, his flatterer and friend had been transformed into the worst of villains, his riches had melted away, the very walls that sheltered him looked on him as a stranger; she alone had turned the same, mild gentle look upon him always. Yes, to the latest and the last. She had never changed to him – nor had he ever changed to her – and she was lost.
However, one day Florence returns to the house with her baby son, Paul, and is lovingly reunited with her father.
Dombey accompanies his daughter to her and Walter's house where he slowly starts to decline, cared for by Florence and also Susan Nipper, now Mrs Toots. They receive a visit from Edith's Cousin Feenix who takes Florence to Edith for one final time – Feenix sought Edith out in France and she returned to England under his protection. Edith gives Florence a letter, asking Dombey to forgive her her crime before her departure to the South of Italy with her elderly relative. As she says to Florence, 'I will try, then to forgive him his share of the blame. Let him try to forgive me mine!'
The final chapter (LXII) sees Dombey now a white-haired old man, 'whose face bears heavy marks of care and suffering; but they are traces of a storm that has passed on for ever, and left a clear evening in its track'. Sol Gills and Ned Cuttle are now partners at the Midshipman, a source of great pride to the latter, and Mr and Mrs Toots announce the birth of their third daughter. Walter is doing well in business, having been appointed to a position of great confidence and trust, and Dombey is the proud grandfather of both a grandson and granddaughter whom he dotes on, and the book ends with the highly moving lines:
'Dear grandpapa, why do you cry when you kiss me?'
He only answers, 'Little Florence! Little Florence!' and smooths away the curls that shade her earnest eyes.