Madam Secretary follows Elizabeth McCord, the shrewd, determined, newly appointed Secretary of State who drives international diplomacy, battles office politics and circumvents protocol as she negotiates global and domestic issues, both at the White House and at home. A college professor and a brilliant former CIA analyst who left for ethical reasons, Elizabeth returns to public life at the request of the President following the suspicious death of her predecessor. The President values her apolitical leanings, her deep knowledge of the Middle East, her flair for languages and her ability to not just think outside the box, but to not even acknowledge there is a box.
When the assistant vice minister of Timor-Leste suddenly dies during a meeting with Elizabeth on the first day of the U.N General Assembly, she becomes suspicious after the president of Timor-Leste ships the body back without a proper investigation. Also, a "fake news" story surfaces claiming Elizabeth is responsible for the minister's death, and Dmitri returns to work with Henry.
With a government shutdown looming, Elizabeth must think outside the box to help fund an electrical grid in a Syrian refugee camp, before riots break out in the country due to the lack of electricity and water. Also, Henry searches for Dmitri when he goes missing.
As the government shutdown shows no sign of progress, Secretary of State McCord must negotiate an agreement between the White House and its opposition led by Senator Morejon. Also, Elizabeth is having trouble finding a suitable replacement for the chief of staff position.
Elizabeth is determined to continue to hold a human trafficking conference in Kyrgyzstan despite the inappropriate actions by a U.S. ambassador. Also, Elizabeth and Henry worry about Alison when she keeps coming home from college.
Henry disagrees with the President and Elizabeth when they refuse to negotiate with terrorists for the release of an American CIA agent who was captured by the Taliban in Afghanistan. Also, Elizabeth tries to be supportive of Stevie who is going through a difficult time.
When a Russian dissident flees to the U.S. after contracting smallpox, Secretary of State Elizabeth McCord and retired U.N. Ambassador Kat Sandoval must work with Russian Foreign Minister Konstantin Avdonin to contain the outbreak
Secretary of State McCord and her staff work with the Mexican government to extradite a Mexican cartel leader to a U.S. prison in an effort to diminish the opioid crisis. But after he escapes during transport and a journalist who secured a gloating interview with him while on the lam is murdered, Elizabeth's urgency to find the leader escalates.
Secretary of State McCord reluctantly agrees to host a holiday party in the hopes of persuading senators in attendance to pass a treaty that requires countries to destroy landmines. Also, Henry tries to find evidence that the Senate Majority Leader exchanged information with the Russians.
Secretary of State McCord struggles with the realization that she may need to advise the Afghan government that a compromise with the Taliban may be better than a war with them. Also, Henry uses Dmitri as bait to convince a Russian spy to help the U.S., and Daisy returns from maternity leave and decides to finally tell Joe's mother about the baby.
When Vice President Hurst feels threatened that Secretary of State McCord is vying to be the next president, she attempts to set Elizabeth up for failure by promising that Americans will continue to be able to adopt Russian orphans, despite the potential ban by Russia's president. Also, Elizabeth and Henry find out Stevie is dating Dmitri after he is followed by a Russian assassin.