Platypus Comix/Tear Jerker

Mulberry

 * Hillary Clinton realizing that even though switching bodies with Mulberry in "Obamadramarama" gives her a second chance to rise to power, refusing to return to her own body will disconnect Hillary from her daughter.
 * Mulberry finally letting the news of Brittany Murphy's death sink in in "Murphy's Lawn".

Electric Wonderland
See Electric Wonderland/Tear Jerker

Keiki

 * Amara endures a number of depressing incidents in "Freewheeling", especially when she discovers that.
 * Peter Paltridge boasts in the Keiki archive that people called this the best comic he made up to that point, but doesn't explicitly say why.
 * Darcy's rant about the media's romanticization of vampires in "Twilight Princess" includes a lament about the fact she can never have a romantic relationship with the mortal Beefer.

Princess Pi

 * Arguably, the part of "Princess Pi vs. The Totally Nazis" when the Totally Nazis' ceaseless insults appear to push Pi over the Despair Event Horizon.
 * "Princess Pi vs. Cerebus Syndrome" plays most of Pi's overly grim stories for laughs, but the story of the death of her mother feels genuinely sad.

Miscellaneous Comics

 * "True Believers":
 * Peter Parker equating the thought of losing Mary Jane with the anxiety previously felt before Marvel released The Night Gwen Stacy Died.
 * Peter and MJ preparing for the moment when Joe Quesadilla will split them up.
 * The part when the fact that Death Is Cheap in the Marvel Universe leaves Spidey doomed to eternally suffer the loss of MJ.

Articles

 * Peter Paltridge's unending suffering in "Kellogg Middle School: The Happiest Place on Earth".
 * The "Concept Unification" video in "The Chuck E. Cheese Story", detailing the transformation of a Showtime Pizza restaurant into a Chuck E. Cheese facility, includes a warning not to watch it because "it's too depressing".