Fernando was educated at St Benedicts Academy (later known as St Benedict's College Colombo) and the Colombo Academy which was later renamed Royal College Colombo. At the Colombo Academy he won the Turnour Prize, Junior Cambridge Scholarship, and Mathematical Prize. He received a Ceylon Government Scholarship and Scholarship from the Gilchrist Educational Trust, enabling him to study medicine at University College London. He graduated with a BSc winning the Atchinson Scholarship and University of London Gold Medals in Physiology, Medicine, Forensic Medicine and Obstetrics. He graduated with an MB in 1888, an MD in 1889 and in 1890 was elected a Fellow of University College London.
On his return to Ceylon he served as Registrar of the Ceylon Medical College and the Superintendent of the De Soysa Maternity Home and was appointed the first Consultant Physician to be appointed to the General Hospital Colombo. He contributed to scientific discussions on a wide range of diseases and is associated with a discussion on Diabetes in the Tropics, where he is credited with the observation that it was more common among the affluent Ceylonese. He was a member of the Ceylon Branch of the British Medical Association, and was Secretary from 1891–1897 and President in the years 1905 and 1914. He was the founding Director of the Bacteriological Institute in Colombo and Chemical Examiner to the Government of Ceylon.
At the age of 43 he resigned from the medical service to take up a career in business and politics. He contested unsuccessfully for the newly created seat (proposed by Sir James Peiris) in the legislative assembly losing to Sir Ponnambalam Ramanathan, but subsequently served on both the Executive Council and Legislative Councils. He supported the Donoughmore Constitution enabling general elections with adult universal suffrage and was largely responsible for devising wider representation to the Eastern Muslims and Northern Tamils.
In 1931 the State Mortgage Bank of Ceylon (the first state-owned bank) was established with Sir Marcus Fernando as its chairman. He also assisted to create the Bank of Ceylon. He, along with Sir James Peiris and Sir Ponnambalam Arunachalam, were instrumental in the creation of the University of Ceylon. He was made a Knight Batchelor in 1923 (New Year Honours List). In 1929 he co-founded the Rotary Club of Colombo.
His father was Andrew Fernando Jr. and his grandfather Andrew Fernando Sr. was the Mudaliyer of Colombo. In 1891 he married Mary Frances, second daughter of Sir Charles Henry de Soysa and had two daughters and a son. Advocate Charles Matthew Fernando, the first Ceylonese Crown Counsel was his brother. His nephews were Chevalier C.H.Z. Fernando, a pioneer labour unionist councillor and campaigner for universal suffrage, the only Ceylonese to have met Lenin, and C. M. Fernando, a founder member of the SLFP.