After college, he joined Kalabhavan, a professional mimicry troupe in Kochi. At the age of 22, he was introduced into the cinema field by script writer and filmmaker Padmarajan who gave Jayaram his launching pad with the 1988 film Aparan. Jayaram subsequently acted in Padmarajan's Moonnam Pakkam (1988) and Innale (1989). Padmarajan became his mentor in his film career till the former's death in January 1991.He became one of the Superstars of Malayalam film industry through the film Meleparambil Aanveedu(1993) which was directed by Rajasenan.
He is noted for playing in Kamal's films during the late 1980s and early 1990s, in films such as Pradeshika Varthakal (1989), Peruvannapurathe Visheshangal (1989), and Shubha Yathra (1990) (all of them scripted by Ranjith), where he co-starred with his wife Parvathy. He later did a film scripted by Ranjith with the story by Jagathy Sreekumar and directed by Viji Thampi named Witness (1988). He teamed up with Viji Thampi and Ranjith in Nanma Niranjavan Srinivasan (1990) where he played a police constable who is in search of a criminal played by Mukesh. During the early 90s he acted in Bharathan's Keli (1991) and Malootty (1992).
He has acted in several of Sathyan Anthikkad's films. Their first film was Ponn Muttayidunna Tharavu (1988). Around that time Jayaram played a supporting role in Sathyan Anthikkad's Ardham (1989). Thalayanamanthram (1990) and Sandesham (1991), were both written and co-starring Sreenivasan. Anthikkad and Jayaram later went on to make Thooval Kottaram (1996), Irattakuttikalude Achan (1997), Veendum Chila Veettukaryangal (1999), Kochu Kochu Santhoshangal (2000), Yathrakarude Sradhakku (2002), Manassinakkare (2003), Bhagya Devatha and Kadha Thudarunnu.
He support acted with Mammootty in Joshi's Dhruvam (1993). Other films with Gopi include Viji Thampi's Nagarangalil Chennu Raparkam (1990), Thooval Sparsam (1990), Jayaraj's Paithrukam (1993), and Sibi Malayil's Summer in Bethlehem (1998). He co-starred with Mohanlal in Bharath Gopi's Ulsavapittennu, Peruvannapurathe Visheshangal (1989) and Priyadarshan's Advaitham (1991).
His association with director Rajasenan created many movies such as Kadinjool Kalyanam (1991), Ayalathe Addeham (1992), Meleparambil Aanveedu (1993), CID Unnikrishnan B.A., B.Ed. (1994), Aniyan Bava Chetan Bava (1995), Aadyathe Kanmani (1995), Swapna Lokathe Balabhaskaran (1996), and Kadhanayakan (1997). He also played Aravindan in Siddique's Friends (1999) in which he co-starred with Sreenivasan and Mukesh. In the first decade of the 21st century his films include Yathrakarude Sradhakku (2002), Manassinakkare (2003), Veruthe Oru Bharya (2008). His roles include Karunakaran in B Kannan's Theerthadanam (2001) and Lonappan in Rajeev Kumar's Sesham (2002).
He also forayed into Tamil cinema including roles in Gokulam, Purushalakshanam, Priyanka, Kolangal, Murai Mamman and Pathini. He played the roles of Dr. Kailash and as Ayyappan Nair in Kamal Haasan starred Thenali and Panchathanthiram. They first came together on screen in Chanakyan (1989). Recently he has done more supporting roles in Tamil, such as antagonist roles in Saroja and Dhaam Dhoom, and a comic role in Aegan.
His movies include Manassinakkare (2003) Njaan Salperu Raman Kutty (2004), Finger Print (2005), Alice in Wonderland (2005), Madhuchandralekha (2006), Moonnamathoral (2006), and Anchil Oral Arjunan (2007). In mid-2008, he played Sugunan in Akku Akbar's Veruthe Oru Bharya (2008) and Thuppakki (2012), which established him as one of the leading comedy actors of Malayalam and Tamil films.
In 2009 he performed in Sathyan Anthikkad's Bhagyadevatha and Happy Husbands. In 2010 he again joined with Sathyan Anthikkadu for Kadha Thudarunnu. In 2011 he was featured in Makeup Man along with comedic roles in Seniors and Chinatown.
Jayaram was born as second among three children to Subramaniyam Iyyer and Thankam at Perumbavoor, Kerala on 10 December 1965. His mother tongue is Tamil. His father is from a Kerala-settled Tamil Iyyer family and his mother is from Thanjavur, Tamil Nadu. He has an elder brother, late Venkit Ram and a younger sister, Manjula. He had his primary education from Government Boys High School, Perumbavoor. He graduated with a B.A. in Economics from Sree Sankara College, Kalady. He became a medical representative soon after college. Later he joined Kalabhavan and performed mimicry in many stages which paved him a way to the Malayalam film industry. Renowned Malayalam writer Malayattoor Ramakrishnan was Jayaram's maternal uncle.
Jayaram got married to actress Parvathy, on 7 September 1992, who is no longer active in films. Their son Kalidas Jayaram is an actor as well who won the National Film Award for Best Child Artist in 2003 for his second movie, Ente Veedu Appuvinteyum. Jayaram also has a daughter, Malavika. Currently he resides at Valasaravakkam, Tamil Nadu with family.Civilian awards2011 – Padma ShriKerala State Film Awards1996 – Special Jury Award – Thooval Kottaram2000 – Second Best Actor – Swayamvara PanthalTamil Nadu State Film Awards2000 – Special Prize – Thenali2000 – Tamil Nadu State Film Award for Best Character Artiste (Male) – ThenaliSouth Indian International Movie Awards2012 — Nominated—Best Comedian – ThuppakkiFilmfare Awards1996 – Best Actor – Thooval Kottaram2001 – Best Actor – Theerthadanam2002 – Best Supporting Actor – Panchathantiram 2003 – Best Actor – ManassinakkareAsianet Film Awards1998 – Best Actor Award – Sneham2001 – Best Actor Award – Theerthadanam, Uthaman2008 – Most Popular Actor Award – Veruthe Oru Bharya2012 – Most Popular Actor Award – Swapna SanchariOther awards1996 – Sini Best Actor Award for Thooval Kottaram1996 – Rotary Club Award for Thooval Kottaram2002 – V. Shantaram Award for his performance in Shesham2008 – J.C Foundation award for the best actor for his performance in Veruthe Oru Bharya2011 – Sathyan Award for Lifetime Achievement2014 – Vayalar Film award for Best Actor for Nadan and Swapaanam2014 – Kerala Kalamandalam M. K. K. Nair Puraskaram