Comeback to Tamil cinema and Debut in TV serials (1999–2014)
After a four-year break from Tamil cinema, in 1999, Ramya played the female antagonist, Neelambari in Padayappa opposite Rajinikanth. The critic from Rediff stated "Ramya does a fantastic job. She is vicious to her dying breath, when she declares she will revenge herself in her next life. She does a fabulous tandav of rage when her father commits suicide". She went onto receive several awards including Filmfare Award for Best Actress - Tamil and Tamil Nadu State Film Award Special Prize. She then starred in commercially successful films like Budget Padmanabhan and Panchatanthiram. The critic from Screen called her performance in Panchatanthiram "one of the finest performances ever".
Ramya has also acted in many devotional films including Rajakali Amman (2000), Nageswari (2001), Sri Raja Rajeshwari (2001) and Annai Kaligambal (2003).
Her notable film in Malayalam was Ore Kadal (2007) with Mammootty, which received the National Film Award for Best Feature Film in Malayalam. She had acted as the mother-in-law of N. T. Rama Rao Jr. in the movie Naa Alludu (2005) marked for her role and later in the film Konchem Ishtam Konchem Kashtam (2009). She also appeared in a guest role in item songs in Tollywood and Kollywood.
She turned to acting in TV serials before hosting a game show called Thanga Vettai, on Sun TV, and judging a dance show, Jodi Number One, on Vijay TV. Ramya is stepping in television serials for the first time. She was seen in Kalasam in two roles. One of them is Neelambari, a character she played in the Rajinikanth starrer Padayappa. In 2009, she appeared in Suresh Krissna's Arumugam and Rama Narayanan's Kutti Pisasu.
She continued her stay under the Sun TV banner to act in Thangam, Vamsam and Rajakumari. Later, she acted in supporting roles in Telugu as Ranga The Donga (2010), Yamudiki Mogudu (2012) and in Kannada as Sweety Nanna Jodi (2013) and Maanikya (2014).