General Tips
- Spend a lot of time collecting blast shards before anything else. It lets you see a bit more of Second Son's virtual Seattle (which looks fantastic), and allows you to purchase useful powers.
- Don't feel like you need to spend blast shards immediately. Some of the later powers require a lot of them, so it never hurts to save up ahead of time.
- Rely on heavy ammo for boss fights, as it makes them a lot more manageable.
- Only begin District Showdowns when you know you're ready. These are large-scale encounters that require planning and patience. Make sure you've unlocked a few handy abilities before you give it a shot.
- Pick Good or Evil Karma and stick with it, so you can get the appropriate powers over the course of your playthrough.
- Traveling through Seattle can be a pain when enemies are constantly hounding the player. Luckily you can fix that by gaining complete control of a district; at that point you can roam the streets without a care in the world.
He Who Dwells Boss Battle
When you face off against "He who dwells," find and hang from a ledge on a platform near him that has a power replenish (do not use it yet, though). Keep firing at your foe (and his summoned angels, if you've reached that point in the battle) while you hang from that ledge. You are able to aim even while dangling, and if you are positioned correctly, none of his attacks will hit you even when he knocks down the columns. Once he is hit enough times, he dissolves and moves to another position, where he appears once more with additional angels at his side. When that occurs, the platform from which you are hanging will sink into the lava. As it does so, grab the power replenish and move to another platform, where you can repeat the cycle. Keep doing this until you win the battle.
Easter Eggs
Cole Macgrath Easter Egg
Head to the Paramount District and you'll find a store called "Cole McG's Electronics," a reference to Cole McGrath (the protagonist in the previous games in the series).
Sly Cooper Ringtone
When someone tries to call you in the game, the ringtone that plays is the theme song from the Sly Cooper games.
Thievius Raccoonis
Near the beginning of the game, you'll wake from a week-long coma. On the table you see on your way to visit Betty, near the X-rays, you'll see a copy of the Thievius Raccoonis, from the Sly Cooper games.
Sly Cooper Mural
Look for Sienna Smith's Play Zone in Seattle, WA. On the back wall, you'll see a mural depicting three raccoons. The one on the left holds a bag of money, the one on the right a gold-handled cane, and the one in the middle is wearing a blue cap. To the side, you should see Sly, Bentley, and Murray depicted as if painted by a child. You can find similar murals elsewhere in the area, as well.
Hotline Easter Egg
Call 1-844-HELP-DUP and you will get a pre-recorded message from Brooke Augustine.
Trophies
| Trophy | Description | Type |
| Enjoy Your Powers | Collect all trophies | Platinum |
| Unstoppable | Finish the game on Expert difficulty | Silver |
| Reconciliation | Finish the story with Good Karma | Gold |
| Rebellion | Finish the story with Evil Karma | Gold |
| Everybody Out | Rescue 10 suspects from suspicion pens | Bronze |
| Spin-off | Beat down 10 sign twirlers | Bronze |
| Everyone's a Critic | Take out 10 street musicians | Bronze |
| Just Say No | Bust 10 drug dealers | Bronze |
| Freedom of Speech | Disrupt 10 activist rallies | Bronze |
| What Did You Call Me? | Kill 10 obnoxious Akuran gang members | Bronze |
| Someone Your Own Size | Rescue 10 escaped conduits from angry mobs | Bronze |
| Walk It Off | Heal 10 wounded civilians | Bronze |
| Kicking and Screaming | Finish off 10 wounded enemies or civilians | Bronze |
| True Hero | Achieve Level 5 Good Karma | Silver |
| Infamous | Achieve Level 5 Evil Karma | Silver |
| Bweep! Bweep! Bweep! | Collect half the Blast Shards | Bronze |
| Shardcore | Collect all the Blast Shards | Silver |
| Nothing to See Here | Destroy half the D.U.P. security cameras | Bronze |
| Blinded | Destroy all of the D.U.P. security cameras | Silver |
| Inside Track | Collect all the Informant Audio Logs | Silver |
| Blown Cover | Defeat all the D.U.P. Secret Agents | Silver |
| Big Brother | Destroy all the D.U.P. Hidden Cameras | Silver |
| Coloring Inside the Lines | Complete all the Stencil Art | Silver |
| Prank Call | Complete a District Showdown | Bronze |
| Hello Operator | Complete Showdowns in half of the districts | Bronze |
| Final Showdown | Complete all of the District Showdowns in the city | Silver |
| One Down | Clear the D.U.P. completely out of a district | Bronze |
| Home Field Advantage | Clear the D.U.P. out of half the districts in the city | Bronze |
| Clean Sweep | Clear the D.U.P. out of the entire city | Silver |
| Total CARnage | Destroy 5 cars in 5 seconds | Bronze |
| Drop Everything | Comet Drop over 170 meters | Bronze |
| Keep It Up | Stay in the air for more than 45 seconds | Bronze |
| Put That Anywhere | Defeat 10 enemies by detonating ammo crates | Bronze |
| Hat Trick | Defeat an enemy using three different power sources | Bronze |
| Double Smoke Stack Attack | Dash through two red air vents without touching the ground and then Comet Drop on an enemy | Bronze |
| Cough Drop | Comet Drop on three coughing enemies | Bronze |
| Make Fetch Proud | Hit three weak points with Neon Beam in 6 seconds | Bronze |
| Excessive Force | Use a Karmic Streak attack to defeat exactly one enemy | Bronze |
| Sacrifice | Risk your freedom to protect those you care about | Bronze |
| Ruthless | Look out for yourself, no matter the consequences | Bronze |
| Temperance | Practice self-control | Bronze |
| Malice | Get them before they get you | Bronze |
| Courage | Stand up for the helpless | Bronze |
| Contempt | Don't fear the weak | Bronze |
| Mercy | Everyone deserves a second chance | Bronze |
| Revenge | An eye for an eye, a tooth for a tooth | Bronze |
| Justice | Expose the corruption of the powerful | Bronze |
| Dominance | Show the world that nobody can protect them | Bronze |
