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In 1997, Simran appeared in the Tamil films *Once More*, *V.I.P.*, and *Nerrukku Ner*, earning the Filmfare Award for Best Female Debut – South. Her breakthrough in Tamil cinema came with roles in *Vaalee* (1999) and *Thullatha Manamum Thullum* (1999), the latter earning her the Tamil Nadu State Film Award for Best Actress. Her Telugu films include *Samarasimha Reddy* (1999), *Kalisundam Raa* (2000), and *Narasimha Naidu* (2001). She also appeared with Kamal Haasan in the comedies *Pammal K. Sambandam* (2002) and *Panchathantiram* (2002), and played an adoptive mother in Mani Ratnam's *Kannathil Muthamittal* (2002), earning the Filmfare Award for Best Actress – Tamil.

After a break from acting, Simran played a mother and wife in Gautham Vasudev Menon's *Vaaranam Aayiram* (2008), earning the Filmfare Award for Best Supporting Actress. She later appeared in character roles in *Petta* (2019), the anthology *Paava Kadhaigal* (2020), *Mahaan* (2022), *Rocketry: The Nambi Effect* (2022), and the Hindi family drama *Gulmohar* (2023).

In 2024, Simran appeared in the Tamil horror-comedy *Aranmanai 4*, the thriller *Andhagan*, and the Amazon Prime Video spy action series *Citadel: Honey Bunny*. Her subsequent credits include the Tamil horror-thriller *Sabdham* (2025), Adhik Ravichandran's action film *Good Bad Ugly* (2025), the drama *Tourist Family* (2025), and the Hindi film *Gabru* (2026).