On his return from UK, he served in many peripheral hospitals as a Consultant Surgeon in the Ministry of Health, Kuliyapitiya, Ampara, Anuradapura, Kalutara and Panadura before embarking on a university academic career. He retired from the university system as the Senior Professor of Surgery and Chair at the Faculty of Medical Sciences, where he also served as the Dean of the Faculty. He was conferred the Professor Emeritus of Surgery on retirement. 

He was a past President of the College of Surgeons Sri Lanka, a former Honorary Consultant General Surgeon, Mid Cheshire Hospitals NHS Foundation Trust, United Kingdom and was a Consultant Surgeon at Colombo South Teaching Hospital from 1998 to 2018.

Prof De Silva is a Fellow of the Asian Pacific Society of Digestive Endoscopy and was a WHO Expert Advisor on Patient Safety in Member States, SEARO, New Delhi, a former member of the Governing Council of the South Asian University, New Delhi, and former representative to USA - Sri Lanka Full Bright Commission.

 He was a past President of the College of Surgeons Sri Lanka, a former Honorary Consultant General Surgeon, Mid Cheshire Hospitals NHS Foundation Trust, United Kingdom and was a Consultant Surgeon at Colombo South Teaching Hospital from 1998 to 2018. Prof De Silva is a Fellow of the Asian Pacific Society of Digestive Endoscopy and was a WHO Expert Advisor on Patient Safety in Member States, SEARO, New Delhi, a former member of the Governing Council of the South Asian University, New Delhi, and former representative to USA - Sri Lanka Full Bright Commission. 

 Prof De Silva is a respected Pancreato-Biliary surgeon who pioneered and established Endoscopic Retrograde-Cholangio-Pancreatic Surgical services (ERCP) and Postgraduate Hands-on-Endotherapy Training programmes in Sri Lanka From 1990s, a service which is well established in the island today. 

 A Respected medical author, teacher, national and international examiner for postgraduate surgical examinations in the UK and Pakistan, he was a single author of a surgical textbook published in the UK titled ‘Clinical Surgery Made Easy - A Companion to Problem Based Learning’, tfm Publishing Limited, Shrewsbury, UK. He is also a chapter contributor to Bailey and Love’s Short Practice of Surgery one of the most widely read surgical test books in the world. He was the first and only Sri Lankan surgeon invited as a chapter contributor for this prestigious text. 

He has delivered 7 orations, has 80 research publications in peer reviewed journals and has won Presidential Award for research. He has delivered large number keynote addresses (141) in local and international conferences in many countries and was an international Resource Person in 13 international surgical workshops.

Prof. de Silva has made an impactful contribution to the progress of General Surgery in Sri Lanka by playing a pivotal role in the introduction of a structured Postgraduate Surgical Training Programme to produce General Surgeons with special Interests. 

He also functioned as the Chairman, University Grants Commission, Sri Lanka from 2015 to Nov 2019.

As the Chairman of the University Grants Commission Sri Lanka, he made a significant contribution to establish a quality, process-driven State Higher Education system and led the strengthening and regularization of the quality assurance processes in the State Universities by establishing a Quality Assurance Directorate in the University Grants Commission. He made a major contribution for preparation and publication of the Gazette for the establishment of the National Quality Assurance and Accreditation Commission for Higher Education, Sri Lanka.

During his tenure of office, he also made a pivotal contribution in bringing the global leaders in Quality Assurance and Accreditation in Higher Education to Sri Lanka, the biennial global conference of International Agencies of Quality Assurance in Higher Education (INQAAHE) in 2019 by a winning country presentation for Sri Lanka at the National Assembly of the International Network for Quality Assurance Agencies in Higher Education (INQAHEE) Conference in Bahrain, beating China and Chile. This conference was attended by Higher Education leaders of 58 countries.

During this period, he provided the leadership to commence two new Medical Faculties in Wayamba and Sabaragamuwa Universities and 12 New Technology faculties in State Universities. He also made a noteworthy contribution to address the lack of safe and conducive learning environment by taking proactive approach to issues on Gender Equity and Equality, Sexual and Gender Based Violence and Ragging in Sri Lankan State universities.

Prof. De Silva served as a Civil Volunteer Surgeon for Sri Lanka Armed Forces from the time of Vadamarrachchi operation in 1987, frequently travelling to Northern and Eastern Theatres of War at short notice and attending to war causalities. This was a time when Army did not have sufficient surgeons in the permanent cadre and most medical personnel were reluctant to travel to North and East.

Prof de Silva was a former Captain of Cricket - University of Colombo in the first division and was the Best All round cricketer of the Year 1978 at the University of Colombo. He is also the recipient of the Lifetime Achievement Award for Most Distinguished Personality produced by Nalanda College Colombo, awarded to one outstanding personality nominated for each school by the 8 ‘Olcott’ schools at the Commemoration of the Colonel Sir Henry Steel Olcott Memorial Sports Foundation 2018.

The prestigious award, ‘The SAARC Surgical Icon of Sri Lanka’, was conferred on Prof. Mohan de Silva in December 2021, during the Annual Scientific Conference of the Association of Surgeons of India (ASICON) after being nominated unanimously by the Council of the College of Surgeons of Sri Lanka and ratified by the Council of the SAARC Surgical Care Society.