Smulders' other films include Safe Haven (2013), The Lego Movie franchise (2014–2019), Results (2015), The Intervention (2016), and Jack Reacher: Never Go Back (2016).

Smulders made her theater debut in the off-Broadway production of the Nora Ephron play Love, Loss, and What I Wore in 2010.

She then made her Broadway debut in the revival of the Noël Coward comedy Present Laughter (2017) earning a Theater World Award.

In 2005, Smulders was cast as television reporter and former teen pop star Robin Scherbatsky in the CBS series How I Met Your Mother.

In June 2010, Smulders made her off-Broadway debut in Delia and Nora Ephron's play Love, Loss, and What I Wore at the Westside Theatre.

She also appeared in the documentary film Being Canadian and guest starred in the NBC variety series Best Time Ever with Neil Patrick Harris.

In 2016, she appeared in the comedy-drama The Intervention starring Melanie Lynskey, Natasha Lyonne, and Alia Shawkat as well as the action adventure film Jack Reacher: Never Go Back, the latter opposite Tom Cruise.

In 2017 she made her Broadway debut portraying Joanna Lyppiatt in the revival of Noël Coward's comedy Present Laughter opposite Kevin Kline.

"[18] David Rooney of The Hollywood Reporter wrote, "Smulders looks sensational; she’s the epitome of late-’30s elegance...she carries herself with poise and assurance".

She also starred as Dexedrine "Dex" Parios, a PTSD-stricken military veteran turned private detective, in the ABC crime drama series Stumptown, which premiered on September 25, 2019 to positive reviews.

[25] In 2020, Smulders starred in the romantic drama film Cicada and voiced a guest appearance in the Fox animated sitcom The Simpsons.

In 2022, she reprised her role of Robin Scherbatsky in the first season finale of the HIMYM spinoff How I Met Your Father, which aired on Hulu.

[27] Also in 2022, she starred in the Amazon Freevee coming-of-age drama series High School, based on the 2019 memoir of the same name by Tegan and Sara.

She had surgery to remove two tumors from her ovaries, but the cancer had spread to her lymph nodes, resulting in the need for multiple operations over the course of two years.

[41][42] In May 2020, she released a clip parodying "Let's Go to the Mall", a song her character performed on How I Met Your Mother, titled "Let's All Stay at Home", to encourage the public to enforce COVID-19 lockdowns.

Smulders also encouraged fans to donate to Save the Children, Canada Helps and the Daily Bread Food Bank amidst the pandemic.