Ok so chances are you've completed every other achievement in the game yet you still need all four of 500-powerups achievements (even if you had the Soul Pet equipped all the way through). Continuing to play until like NG+7 or something is tedious. Farming Arena is also inefficient. Here's how you can do it faster.

Wherever you are currently in the main game, play until you reach episode 3. Hopefully you're not that far. Some of the episode 3 levels contain guaranteed powerups right next to the spawn. The idea is that you grab the powerup and immediately quit the level (or die), then rinse and repeat until you get the achievement. It's actually not that bad with such a method.So here's what you do.

1. Reach episode 3.
2. Clear Moon Terror first, i.e. go for the spacestation-looking exit and beat 3 levels.
3. Once you go back to Wastelands-2 there will be a collection of guaranteed powerups in the area (1 Reflection, 2 Horse Waters, 1 Nightmare Reaper, and 3 V's). Technically you could start farming here but they are all pretty far from the spawn so I recommend to skip this area for now.
3. Clear Fields of Death next, i.e. go for the exit by the tank and beat 3 levels.
4. Once you go back to Wastelands-3 there will be a Horse Water and a Reflection hanging above the tank - right by the spawn. Farm those until you get both achievements. It is important that you beat Fields of Death after Moon Terror.

5. Keep playing through all of the Sorcerer's Mansion hub and its sub-areas.

6. Reach the third hub, Buried Ruins 1. There is a Nightmare Reaper directly at the spawn (where you fight two bosses). You know what to do.
7. Complete Flesh Pits first, e.g. go for the creepy pink throne-like exit and beat 3 levels. Don't go for the other exit or it won't work.
8. Once you go back to Buried Ruins 2 there will be a V powerup directly at the spawn.

Let me sum it up again. Here are the guaranteed powerups located directly near the spawn (provided you beat the levels in the correct order):

Also, there's this additional possibility:

Originally posted by kome360:

Also, I can confirm that using the Low-Health Nightmare Reaper ability counts. Get a rapid-fire blood ammo weapon and spray for your life.

You can potentially farm V's at Wastelands-2 and combine it with this method for Nightmare Reaper, thus having to only play through hub 1/3 without reaching hub 3/3 if you want. Or you can just stick to everything written above.

Thanks to Yaridovich, SexyPanther, kome360, NeighMeansNeigh for contributing to the guide.