R.G. Senanayake left his legal practice and entered mainstream politics in 1943, when he contested a by-election for the Naranwala electorate, which had been made vacate by the sudden death of his brother-in-law Siripala Samarakkody. He was elected from Naranwala to the State Council of Ceylon.
Following the sudden death of D.S. Senanayake, his cousin Dudley Senanayake succeeded his father as Prime Minister. The new Prime Minister offered R.G. Senanayake the post of Minister of Trade and Commerce. As Minister of Trade and Commerce, R. G. Senanayake initiated many of the first major post-independence trade policies such as the Ceylon-China Rubber-Rice Pact and the tripartite Trade agreement between Ceylon, Egypt and Japan. He initiated the Ceylonese enterprise in commerce that was dominated by Europeans in the British colonial era. The Ceylon-China Rubber-Rice Pact, signed in 1952, which had a five year term and renewable proved to be a cornerstone Ceylon foreign policy, establishing close relations with the Peoples Republic of China and Sri Lanka. The pact was beneficial to Ceylon that depended on rice exports, but came into conflict with the pro-western government. He continued to hold the post of Minister of Trade and Commerce under his cousin SirJohn Kotelawala, who succeeded Dudley Senanayake. However, he opposed Kotelawela's plans to join the South East Asia Treaty Organisation, which resulted in Kotelawela dropping the idea. He further opposed Kotelawela's plans to grant citizenship to foreigners. With mounting differences of opinions, notably with tension mounting between United National Party strongman and distant relative J. R. Jayawardene, Senanayake resigned his Ministerial portfolio on 10 July 1954 and was later expelled from the United National Party.
Independent candidate
As an independent candidate, he contested the 1956 general election from two constituencies Kelaniya and Dambadeniya. He won in both, defeating J. R. Jayewardene in the Kelaniya electorate. Re-elected to parliament, Senanayake now represented two electorates, a first in Ceylon. However the Attorney General ruled that he was entitled for only one vote and allowance.
Minister of Trade and Commerce
He joined the government of S. W. R. D. Bandaranaike, having been appointed again Minister of Trade and Commerce. He along with Philip Gunawardena, Minister for Agriculture and Food; was instrumental in convincing Bandaranaike to award the lucrative shipping contract to import rice from Burma and Thailand to the government own Ceylon Shipping Corporation and lucrative sugar manufacturing contract to the government Sugar Cooperation, preventing these going to companies created by Mapitigama Buddharakkitha Thero and his associate H. P. Jayawardene. This was found to be the reason for the assassination of Bandaranaike in 1959. Following the assassination, Senanayake served under his successor W. Dahanayake as Minister of Food, Commerce and Trade.