In the spring of 1957 newly qualified midwife Jenny Lee arrives in the East End of London to begin her career. After overcoming the initial shock that her new home, Nonnatus House, is a convent rather than a private hospital she quickly becomes immersed in her new life. Living with Nuns and working in a community of colourful characters, such as Conchita Warren and her 25 pregnancies, is different from anything Jenny has encountered previously. Through her we experience the sorrows and joys which come with being a midwife.

As Jenny Lee settles into her role, there is a new arrival at Nonnatus House, Chummy (Miranda Hart) . A welcome pair of extra hands Chummy sets about showing her worth, but an overwhelming keenness to please and her inability to ride a bike prove obstacles in gaining the respect of Sister Evangelina. Meanwhile a chance encounter with Mary, a young pregnant runaway, forces Jenny to see an unfamiliar darker side of life.

Jenny is placed on the district nursing roster for a few weeks, to extend her experience of community practice. During her rounds she attends to Joe, a gentle old soldier, and a friendship forms. At the antenatal clinic Trixie and Cynthia enrol Winnie Lawson as new patient. In her forties Winnie had thought her days of nappies and babies were long gone, and seems upset by her pregnancy. By contrast her husband Ted is overjoyed by the news. However at the baby's birth everyone gets a bit of a surprise.

A baby girl, recently delivered by Jenny, is snatched from her pram, causing great anguish to her family and uniting the local community as they search for the missing child. Meanwhile Cynthia witnesses another type of loss as she assists in the case of soon-to-be parents David and Margaret. Newly married and excited about their future, everything is put in jeopardy when Margaret develops eclampsia.

An episode in which Jenny finds herself for once not involved in the beginning of life, but at it's end. When Frank, the brother of Peggy the cleaner at Nonnatus House, is diagnosed with cancer Jenny and the nuns are called upon to provide him with care. In doing so Jenny comes to know the siblings better, learning of their upbringing in a workhouse and the profound effect it has had on their relationship. As Jenny tends to Frank, the other residents of Nonnatus House find themselves involved in helping Fred with his latest money making venture - a pig called “Evie”. Fred's plan had been to make his fortune from bacon, this is scuppered when it's realised the pig is pregnant. The nuns and nurses help out Fred and Evie in the manner they know best.

[Season Finale] Sister Monica Joan is found wandering near the docks, and returned to Nonnatus House by the police. Her adventure takes its toll on her health and she succumbs to pneumonia. When she eventually recovers she sails forth back into the community only to find herself in trouble with the law when she is accused of theft. Chummy has further worries when her mother decides to make a trip to inspect her new "beau".