[7][10] Her first stint with acting happened on Gujarati stage when she was 10; her school teacher's playwright husband asked Shah's mother if she would permit her daughter to play a character based on Damien Thorn from The Omen (1976).

[14][16] Shah opened a restaurant named Jalsa in Ahmedabad, Gujarat in 2021, which serves Indian and international cuisines and offers customers different cultural and recreational activities, from pottery and henna decoration to musical performances such as Garba.

[61] Shah played Rhea Verma, an orphaned young woman, aspiring writer and a survivor of child sexual abuse, a character she considered as the most complex in the film.

[67][68] Shah worked again under her husband Vipul's direction in the family melodrama Waqt: The Race Against Time (2005), playing Amitabh Bachchan's wife and Akshay Kumar's mother.

[72] Her portrayal of Sumitra Thakur, a strict mother who encourages her husband to take extreme measures to discipline their irresponsible son, earned her a second Filmfare nomination for Best Supporting Actress.

Derek Elley of Variety and Ziya Us Salam of The Hindu commended her subtle and composed acting,[73][74] and Subhash K. Jha of The Times of India argued that "it's Shefali Shah as Amitabh Bachchan's wife whose expressive eyes conveying spousal and matriarchal pain that you come home with".

[82][83] Khalid Mohamed of Hindustan Times called her performance "magnificent" and Roshmila Bhattacharya of Screen described her as "brilliant, her sparkling glances, eloquent silences and drooping shoulders effectively conveying the hopelessness and helplessness of a parent whose child has gone astray".

Subhash Ghai's crime thriller Black & White (2008) stars Shah as Roma Mathur, a Bengali activist and the wife of an Urdu professor (Anil Kapoor).

[98][99] Two years later, in view of the lack of substantial film work that would realise her acting potential, Shah's husband Vipul cast her in his Hindi stage production Bas Itna Sa Khwab, directed by Chandrakant Kulkarni.

[111] After three years of absence from the screen, Shah returned as Jyoti, a brothel madam in Nagesh Kukunoor's 2014 social problem film Lakshmi, alongside Monali Thakur.

[112][113] Based on the true story of a teenager who is kidnapped and sold into a brothel in Hyderabad,[112] Lakshmi released to a positive critical reception for its harshly realistic depiction human trafficking and child prostitution.

[116][117] In 2015, Shah starred in Zoya Akhtar's comedy-drama Dil Dhadakne Do alongside Anil Kapoor as her husband, and Priyanka Chopra and Ranveer Singh as her children.

[118] The story is about a wealthy, dysfunctional family who embark on a cruise to celebrate the 30th wedding anniversary of the parents; Shah played Neelam Mehra, the passive-aggressive matriarch caught in a marriage of convenience and hiding her eating disorder.

[118][119][120] Shah loved the script and the character but was initially apprehensive about accepting another part of a middle-aged woman and playing a mother to Chopra and Singh; she eventually relented on her husband's advice.

[123][124][125] Subhash K. Jha found Shah's performance the most effective of the ensemble cast, arguing she "brings to her character an unfussy pitch-perfection rarely seen in mainstream cinema".

[130] The film generated mixed-to-negative reviews;[131] Vishal Menon of The Hindu thought she had a role which required copious crying but The Hollywood Reporter found her performance heartbreaking.

[144][148] "Each episode [in Delhi Crime] moves along at a lightning fast pace and at the centre of it is the brilliant Shefali Shah, who is like a tornado that blows through every scene and leaves a permanent mark.

[163][164] In Someday, which marked her directorial debut, she played a frontline healthcare worker who returns home for a seven-day quarantine due to the pandemic and spends time interacting through a door with her elderly mother, who suffers from Alzheimer's disease.

[72][169][171] The 2021 Netflix original anthology film Ajeeb Daastaans, comprising four short stories, featured Shah in the fourth segment "Ankahi", directed by Kayoze Irani.

Directed by her husband for Disney+ Hotstar, the show explores the nexus between pharmaceutical companies and large private hospitals who conduct human trials for new drugs on lower-class citizens.

[177] Hindustan Times described Gauri as one of the best characters on Indian digital series yet, calling her an "incredibly disturbed sociopath" and "a vicious snake singularly committed to building her business".

[183] Anuj Kumar of The Hindu commended Shah and her character: "At the cost of repeating oneself, the depth of Shefali's eyes and the emotions that they could hold continues to bewitch and baffle.

"[184][185] In the black comedy Darlings (2022), produced for Netflix, Shah and Alia Bhatt star as a mother and daughter who embark on a revenge plan against the latter's abusive husband.

[192] August 2022 saw the release of the second season of Delhi Crime, based on the chapter "Moon Gazer" from retired police officer Neeraj Kumar's book Khaki Files.

[194][195][196] According to Vogue's Taylor Antrim, Shah is "tremendous in the role" as she "seizes your attention" in her reprisal of Vartika Chaturvedi, who is "intensely serious; fearsome to her subordinates, who call her 'Madam Sir'; and clearly burdened by her job".

[198] Shah next appeared as a strict physician in the medical comedy Doctor G, alongside Ayushmann Khurrana and Rakul Preet Singh, for which she was nominated for the Filmfare Award for Best Supporting Actress.

[199][200] The drama Three of Us (2023), directed by Avinash Arun, stars Shah as Shailaja, a woman who, after being diagnosed with early-stage dementia, decides to make a trip to revisit her childhood and confront her past.

[70][105] Her first roles on television when she was in her early twenties, including Savy, the mother of a teenager in Hasratein, made several filmmakers offer her parts of women that far surpassed her actual age.

[217][218] Following the positive reaction to her performance in Satya in 1998, she expected more film work coming her way whereas the offers she received at the time comprised mostly small character parts.

[185] Author and journalist Aparna Pednekar wrote, "Shah's au naturale performances come from an instinctive, savage space, with an abundance of layers simmering beneath a placid smile and soft-spoken personality".