When the Indonesian National Revolution broke out, Leimena had been working at a hospital in Tangerang.
He accepted an offer to become a Junior Minister for Health in the Second Sjahrir Cabinet formed in 1946, under Health Minister Darma Setiawan.
Leimena was first appointed as a full health minister in the First Amir Sjarifuddin Cabinet, which was formed on 3 July 1947.
He retained the post for the rest of the revolution and several years after, until 1953 when the Wilopo Cabinet collapsed for a total of eight cabinets.
Leimena was also a founding member of the Indonesian Christian Party (Parkindo), being appointed as part of the leadership committee upon Parkindo's formation in September 1947.
He would later be elected as Parkindo's chairman following the party's 3rd Congress on 6–9 April 1950.

Beyond his cabinet position, Leimena agreed to chair the Pemuda Indonesia Maluku (PIM), a pro-Indonesian Ambonese organization formed by Johannes Latuharhary.
While both Leimena and Latuharhary were respected, they held little control over PIM's activities.
Leimena was initially based in Jakarta in the early days of the revolution, but moved alongside the rest of Sjahrir's cabinet in 1946 to Yogyakarta as Jakarta was being increasingly controlled by the Dutch.
Leimena was an important member of the Indonesian negotiating team in agreements with the Dutch.
He was part of the Indonesian delegation to the Linggadjati Agreement of November 1946, and the Renville Agreement of January 1948 (during which, Leimena remarked, the Indonesian side accepted the Dutch terms under American pressure).
After the Dutch Operation Kraai Leimena evaded capture and attended talks in Jakarta with representatives from the federal states of the United States of Indonesia in January 1949.
During the Roem–Van Roijen Agreement, Leimena also participated in negotiations, and he further participated in the Dutch–Indonesian Round Table Conference in Den Haag, leading Indonesia's military delegation.

When the South Maluku Republic (RMS) was declared in Ambon in the aftermath of the Dutch recognition of Indonesian sovereignty, Leimena was dispatched to Ambon to lead the Indonesian government's initial negotiating party ("Leimena mission") with RMS leaders aboard the corvette Hang Tuah.
While Leimena attempted to convince RMS leaders in Ambon (where they arrived on 1 May 1950) and Saparua to come aboard Hang Tuah to negotiate, the leaders refused, wanting to negotiate on board neutral vessels while under United Nations supervision.
Additionally, the RMS leaders wanted to be recognized as representatives of an independent state, a request that was refused.
Leimena had initially intended to travel to Ambon aboard a KNIL aircraft, but this was overridden by the Defense Minister at that time.
After further attempts at negotiation failed, tensions continued to rise between the Indonesian government and RMS, with another attempt in June endorsed by Leimena failing due to difficulty in securing transport.
A last-ditch attempt at establishing contact was attempted by sending Leimena to Namlea on 27 September, reportedly giving him wide authority in the negotiations including amnesty and autonomy for the region, but the mission was interrupted by TNI's landings in Ambon the day after Leimena's departure.
When the Indonesian National Revolution broke out, Leimena had been working at a hospital in Tangerang. He accepted an offer to become a Junior Minister for Health in the Second Sjahrir Cabinet formed in 1946, under Health Minister Darma Setiawan. Leimena was first appointed as a full health minister in the First Amir Sjarifuddin Cabinet, which was formed on 3 July 1947. He retained the post for the rest of the revolution and several years after, until 1953 when the Wilopo Cabinet collapsed for a total of eight cabinets. Leimena was also a founding member of the Indonesian Christian Party (Parkindo), being appointed as part of the leadership committee upon Parkindo's formation in September 1947. He would later be elected as Parkindo's chairman following the party's 3rd Congress on 6–9 April 1950.
Beyond his cabinet position, Leimena agreed to chair the Pemuda Indonesia Maluku (PIM), a pro-Indonesian Ambonese organization formed by Johannes Latuharhary. While both Leimena and Latuharhary were respected, they held little control over PIM's activities. Leimena was initially based in Jakarta in the early days of the revolution, but moved alongside the rest of Sjahrir's cabinet in 1946 to Yogyakarta as Jakarta was being increasingly controlled by the Dutch. Leimena was an important member of the Indonesian negotiating team in agreements with the Dutch. He was part of the Indonesian delegation to the Linggadjati Agreement of November 1946, and the Renville Agreement of January 1948 (during which, Leimena remarked, the Indonesian side accepted the Dutch terms under American pressure). After the Dutch Operation Kraai Leimena evaded capture and attended talks in Jakarta with representatives from the federal states of the United States of Indonesia in January 1949. During the Roem–Van Roijen Agreement, Leimena also participated in negotiations, and he further participated in the Dutch–Indonesian Round Table Conference in Den Haag, leading Indonesia's military delegation.
When the South Maluku Republic (RMS) was declared in Ambon in the aftermath of the Dutch recognition of Indonesian sovereignty, Leimena was dispatched to Ambon to lead the Indonesian government's initial negotiating party ("Leimena mission") with RMS leaders aboard the corvette Hang Tuah. While Leimena attempted to convince RMS leaders in Ambon (where they arrived on 1 May 1950) and Saparua to come aboard Hang Tuah to negotiate, the leaders refused, wanting to negotiate on board neutral vessels while under United Nations supervision. Additionally, the RMS leaders wanted to be recognized as representatives of an independent state, a request that was refused. Leimena had initially intended to travel to Ambon aboard a KNIL aircraft, but this was overridden by the Defense Minister at that time. After further attempts at negotiation failed, tensions continued to rise between the Indonesian government and RMS, with another attempt in June endorsed by Leimena failing due to difficulty in securing transport. A last-ditch attempt at establishing contact was attempted by sending Leimena to Namlea on 27 September, reportedly giving him wide authority in the negotiations including amnesty and autonomy for the region, but the mission was interrupted by TNI's landings in Ambon the day after Leimena's departure.
Johannes Leimena