Santhanam started his career on television with the comedy show Lollu Sabha, which became a massive hit and showcased his talent for parody and satire. His success on TV opened doors to Tamil cinema, where he quickly became one of the most sought-after comedians. Films like Siva Manasula Sakthi (2009), Boss Engira Bhaskaran (2010), and Oru Kal Oru Kannadi (2012) established him as a comedy superstar.
Over time, Santhanam successfully transitioned into lead roles, proving his versatility beyond comedy. Movies such as Vallavanukku Pullum Aayudham (2014), Dhilluku Dhuddu (2016), and Sabapathy (2021) highlighted his ability to carry films as the main hero. His journey from a supporting comedian to a bankable lead actor is considered one of the most inspiring success stories in Tamil cinema.