- The colony on Virinat is destroyed by the Elachi and Tal Shiar.
- The Borg start their first incursion into the Alpha and Beta Quadrants in more than 30 years, most notably on Defera Prime and Vega IX.
- Daniels recruits temporal agents from the 2257 and 2270 and brings them to 2409.
- House Mo'Kai, led by Matriarch J'Ula, arrives from 2257.
- Franklin Drake escapes Klingon custody.
- The Federation-Klingon War, in its 4th year, rages across the border areas. Ambassador B'vat attempts to use illegal weapons and time travel to secure a Klingon victory.
- The Fek'Ihri return to attack Qo'noS.
- The House of Torg gets dissolved.
- The Romulan Insurgency ends, beginning the Romulan Civil War.
- The Romulan Republic, a faction formed by D'Tan, settles on New Romulus.
- Devidian incursions on and near Drozana Station lead to an investigation that reveals that Devidians have been feeding on crews from the 23rd century. The incursions are ended with the destruction of Driffen's Comet
- The Federation and Klingons send crews to Nimbus III to track down thalaron triggers.
- Empress Sela attempts an invasion of Vulcan.
- The Romulan Star Empire is found to be experimenting with Borg technology.
- Former Empress Taris is captured and her Iconian gateway destroyed after her involvement in the Hobus supernova is discovered.
- Reman with aid from Federation/Klingon forces, defeat Sela and Hakeev's base on Brea III.
- Sela is kidnapped by the Iconians.
The below could potentially take place in 2410.
- The True Way form an alliance with Admiral Leeta of the Mirror Universe.
- Deep Space 9 is occupied by temporally displaced Dominion forces.
- The Romulan Tutorial ( “A Day on the Farm”) is said to occur in January 2409, two weeks before the Starfleet tutorial ( “Graduation Day”). The Klingon tutorial ( “End of Watch”) is undated, but presumed to occur around the same time, but “Friend or Foe” presumably concludes before the original mission order of “Skirmish” in the Klingon War arc due to Franklin Drake's presence.
- “Devil's Choice” and “Shadow Play” occur at the same time, meaning the Vengeance and Romulan Mystery arc run roughly in parallel, with no KDF events happening between “Alpha” and “The Vault”.
- “Cutting the Cord” is the last event certain to have taken place in 2409.
- Some mission chains are not unlocked until endgame, but are set in 2409;
- Wasteland is not unlocked for Federation and KDF players until endgame, but occurs at the same time (before “The Vault”) in the game's story as it does for Romulans.
- Lost Dominion and Cold War and Spectres were originally set in 2409, although are now not playable until Level 65. In terms of timeline, Lost Dominion occurs at the end of Cardassian Struggle and is immediately followed by Cold War, while Spectres occurs during the Klingon War arc.
- Alexander Rozhenko, son of Worf
- Borg Queen
- Admiral B'vat, son of Warat
- Colonel Hakeev
- M'ven, son of Drex
- Ambassador Sokketh
- S'gen, son of Torg
- Captain Taggart
- Commander Temer