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In 1908 Agnes Towler, a shop girl at Gamages store, is sacked after a flamboyant American customer insists she empty her entire stock of gloves on her counter but later receives an expensive pair of gloves from the man. He is Harry Selfridge, a former shop worker who has moved from Chicago to London with his mother Lois, wife Rose and their children. His aim is to open his own store in Oxford Street. When his original partner backs out journalist Frank Edwards introduces Harry to influential suffragette Lady Mae Loxton, through whom he obtains the required financial backing. In March 1909 he opens his unprecedently sumptuous new department store. He employs Agnes, making her senior accessories assistant, which annoys fellow shop girls Doris and Kitty, though Victor, a waiter at the store's restaurant, takes a shine to her. Also on the staff are chief accountant Mr Crabb, stoic chief of staff Mr Grove, head window dresser Henri Leclair, the formidable Miss Mardle, head of accessories and Miss Bunting, her nervous counter part in fashion. Frank also introduces Harry to Gaiety girl Ellen Love, who, as the opening is launched, is chosen to personify the Spirit of Selfridges.

Agnes gets her younger brother George work in the warehouse at the store but the siblings get a nasty shock when their brutish, drunken father Reg turns up and they reluctantly let him stay. Feeling alienated from her husband's business Rose goes to the National Gallery and strikers up a friendship with handsome young artist Roddy, though she is taken aback when he makes a pass at her. The store is not doing as well as Harry had hoped and he needs a gimmick to attract trade. He therefore approaches the cross-Channel aviator Louis Bleriot and display Bleriot's plane at Selfridge's. This is a huge success with Ellen Page sitting in the cockpit modelling flying scarves - which sell out as a result. Lady Mae asks for a free suit for her young lover Tony, reminding Harry of his debt to her whilst Harry himself, though determined to give Rose more attention, is caught in a compromising situation in Ellen's dressing-room. After this he buys her a house in St. John's Wood.

Harry continues his affair with Ellen in her new home but Rose visits Lady Mae, who alerts her to her husband's infidelity, causing Rose to agree to pose for a painting by Roddy. Harry shocks his staff by suggesting that all beauty products should be put on display, rather than behind the counter, with perfumes at the fore to mask street smells. Display organizer Henri brings in his old flame, Valerie Maurel, an advertising agent for consultation and, although she hints at caution, Harry gets his way. However Henri also sees that Agnes has a talent and uses her designs and not Ellen's photographs in the display window. Agnes is experiencing domestic troubles though, due to Reg's drinking. Lady Mae forces Harry to cancel Tony's gambling debts as well as getting him to support the Suffragette movement by allowing them to meet weekly at the store.

Whilst Mr Grove - married to an invalid wife - and Miss Mardle continue their affair Miss Bunting is dismissed for stealing and replaced with the progressive Ravillious, whose new-fangled ideas annoy many staff members. Harry arranges for visiting Russian ballerina Anna Pavlova to come to the store as a publicity stunt. Rose misses the event as she is at the Chelsea Arts Club with Roddy but finally reveals to him that she is Mrs Selfridge and resists an affair. Ellen Love attempts to upstage Pavlova and is dumped by Harry. Another unwelcome diversion is the arrival of drunken Reg Towler, who is thrown out by Victor. He wants Agnes to live with him but she refuses and leaves the store.

Victor visits Agnes and they kiss. Harry also pays her a call and persuades her to go back to work, buying off Reg and threatening him not to return. Roddy goes to see Rose with a portrait he has painted of her. They too kiss and are seen by Rose's daughter Beatrice, whom Rose swears to secrecy though she tells her father about the portrait. Rose is also visited by Ellen, who is blatant about her affair with Harry though Rose tells her she already knows of it. Victor is disappointed that Agnes is working close to Henri but steps in to save George's job when Harry discovers a scam in the warehouse. Lady Mae, having tired of Tony, turns her attentions to Victor. Harry gets drunk at his club where Ellen arrives, saying she loves him. However he dismisses her and, drunk, crashes his new car into a tree whilst Frank discovers Ellen unconscious after taking an overdose of tablets.

Harry lies in a coma and journalists are keen to know why he was driving, drunk, late at night. Frank tells Lois of Ellen's outburst and insists they keep it quiet, also instructing the recovering Ellen to stay away. Victor is late for work after being bedded by Lady Mae and Mr Grove turns up despite his wife's recent death. All past animosities among the shop girls are forgotten as everybody pulls together in Harry's absence and Agnes and Henri grow closer. The staff meet to discuss a forthcoming march past Selfridge's by the suffragettes on the day the group meet there for lunch. Grove, who opposes votes for women, insists the meeting be cancelled, antagonizing Lady Mae. The more far-sighted Mr Crabb, sensing that Selfridge's should be linked to progress, over-rules him and orders a window display in support of women's rights. Recovering from his coma Harry arrives at the store to take credit for the display and find his daughter Violette among the marchers.

Während einer Signierstunde bei Selfridge überredet der bekannte Schriftsteller und Spiritist Sir Arthur Conan Doyle Harry dazu, im Kaufhaus eine Séance abzuhalten.

Harry hosts a dinner for fellow American Frank Woolworth, who has opened a chain of discount stores in the United States and is extending his business to London. Seeing the need to compete with Woolworth Harry plans a lavish mid-season bargain sale. Kitty and Doris are interviewed by Grove for promotion to replace Agnes and Grove asks Harry to consider a reference for Miss Bunting. Harry refuses but Grove is touched by Doris's humanity and homeliness. Ellen Love comes to the store with Tony to invite the Selfridges to the opening night of his play, in which she will star. Victor asks Lady Mae for the capital to open his own restaurant and is crushed when she refuses. Agnes goes on a date with Henri, staying the night with him and next day touring the markets for ideas to promote the sale. On returning home she meets a disappointed Victor waiting for her. On Sunday the Selfridges go to church but Rosalie, feigning illness, stays at home. Returning early Rose is shocked to find her with Roddy, whom she has met through Lady Mae, and tells him to leave.

News reaches the store that Miss Bunting has killed herself, causing a remorseful Harry to offer to pay for her funeral and Mr Grove to take an upset Doris out for tea, claiming he should have done more to help. Agnes and Henri also discuss the suicide and reach out for each other but they are interrupted by Miss Ravillus, who warns Agnes to be careful about the relationship and consider her career. When Valerie reappears at the store Agnes gives Henri her blessing to see her and gets on with the window display marking explorer Ernest Shackleton's lecture to be given at Selfridge's. Unemployed, Frank is refused a job by Harry and goes to see Ellen, about to open in Tony's play. Victor, aware that Lady Mae has used him, tells her what he thinks of her and, at the Shackleton exhibition, Harry is annoyed to see Rosalie with Roddy - and even more so when the young artist tells him that he and Rose were once in love.

Harry wakes up in bed with a one night stand and returns home to an unwelcoming Rose. On arriving at work he is told by Lady Mae that the king wants a private shopping session after hours. Doris has her own good news. Grove has asked her to marry him but Miss Mardle is shocked and insulted when he suggests they continue their affair. Henri tells Agnes that he will be going to New York to work with Valerie. Harry is angry at losing such a valued employee and insists he goes immediately. Agnes is disappointed but finds consolation with Victor. The king's shopping trip is a success and he invites the Selfridges as his guests to see Ellen's new play. However the play, whilst approved by a gloating Frank, is a cruel satire directed against Mae - lampooning her predilection for young men - and the Selfridges, picking on Harry's greed and Rose's dalliance with Roddy. Back home Rosalie is appalled and rows with her mother over Roddy but this actually leads to a truce and rapprochement between Mr and Mrs Selfridge.