After the 2000 parliamentary elections in which SDP, under Ivica Račan, won in a broad coalition, Picula was appointed Minister of Foreign Affairs and served a full term until 2003.

During his term in office, Croatia had several important foreign-relation successes, including becoming a candidate for NATO and the European Union and joining World Trade Organization.

After years of negotiations, disagreements and delays he also signed the Agreement on Succession Issues of the Former Socialist Federal Republic of Yugoslavia on behalf of Croatia.

He was appointed as a special coordinator and head of OSCE observation missions to the parliamentary and presidential assemblies in Moldova (2010), Kazakhstan (2011), Russia (2012), Georgia (2012) and Armenia (2013).

[22] As vice-president of the Delegation of the European Parliament for relations with Southeast Europe, Tonino Picula went on his first official mission to Albania and Kosovo, and also stayed in Bosnia and Herzegovina, Macedonia and Montenegro.

Due to the deterioration of the political and security situation, he stayed in Kyiv and Kharkiv three times as part of the Ad hoc Delegation of the European Parliament.

At the invitation of the Office of the European Parliament in Washington, he presented Croatia's entry into the EU during talks at the State Department, the Pentagon, Congress, the World Bank and foreign policy foundations.

The focus of IPA III is on key reforms in the rule of law, economic transformations and harmonization with European standards, with the aim of strengthening democracy, socio-economic development and regional cooperation.

As the coordinator of S&D in the field of foreign policy, Tonino Picula played a key role in creating the Resolution on Russian aggression against Ukraine.

In his capacity as chief negotiator, Picula had a decisive influence on the Resolution which clearly condemned the invasion of Ukraine and supported its resistance to the aggressor.

The resolution encouraged diplomatic efforts to stop the aggression, provide urgent humanitarian aid to Ukraine and strengthen its defense capabilities.

[30] In August 2013, MEP Picula asked the European Commission to clarify the situation regarding Croatian autochthonous wines: Prošek and Teran.

He also supported the rejection of the Commission's proposal in the discussion on the production and making available on the market of seeds and other plant reproductive material, as this would contribute to an additional oligopoly of the largest companies.

Picula, as a substitute member of the Committee for Agriculture and Rural Development (AGRI), organized a round table in Zagreb dedicated to the new European Union regulation on labels of origin, which also has an impact on the future of the Croatian Prošek case.

He called on the European institutions to adjust the legislation in order to preserve the unique heritage of small-scale fishing, and as a continuation of that initiative, he organized a TV panel in Brussels, where representative Guido Milana, vice-president of the Fisheries Committee, announced a revision of European legislation that will elaborate the special nature of small-scale fishing.

During the 7th and 8th Parliamentary terms he served as the Chair of the European Parliament delegation for relations with Bosnia and Herzegovina, and Kosovo (2014–2019), substitute member of the Delegation to the EU-Serbia Stabilisation and Association Parliamentary Committee (2014–2019), and was responsible on behalf of the S&D Group for a number of reports such as those on the Accession Agreements with Ukraine and with Northern Macedonia,[31] and the European Defence Union.

[33][34] The project was started by MEP Picula in collaboration with Christian Pleijel from the Royal Institute of Technology in Stockholm with the aim of promoting the concept of smart islands and establishing them as a source of sustainable water saving solutions.

Two of Tonino Picula's initiatives are aimed at combating misinformation and promoting media literacy, among young people and among the retired population.

In six retirement homes across Croatia, including Rijeka, Vrgorac, Zadar, Zagreb, Šibenik and Konavle, the lectures were attended by as many as 350 seniors.

The project initially gathered 8 islands from 4 different EU member states: Lastovo and Vis from Croatia, Houat and Sein from France, Ithaka and Tilos from Greece, Cape Clear and Inis Oirr from Ireland.