Most probably yes, but in most cases you won't be even able to notice the difference.
Edit: I see that people don't like my answer :). Maybe because it's simple. IMHO it doesn't make it less true. Well… prove me wrong :).
Edit 2: I wanted to keep my answer brief but… :)
Q: In Photoshop, will there be a difference in quality when a raster is scaled down 75% once as opposed to being scaled down 50% twice? In both cases, the final size will be the same: 25% of the original.
A:
"Most probably yes" – take a look at muntoo's post. He says that each interpolation step introduces some minor errors. They are rounding or representaion errors and they can contribute to quality degradation. Simple conclusion: more steps, more possible degradation. So "most probably" image will loose quality during each scaling step. More steps – more possible quality degradation. So "most possibly" image will be more degraded if scaled in two times than in one. Quality loss is not certain — take a solid color image for example, but how often will any designer scale similar images?
"but in most cases you won't be even able to notice the difference" – again – muntoo's post. How big are potential errors? In his examples are images scaled not in 2 but in 75 steps and changes in quality are noticable but not dramatic. In 75 steps! What happens when image is scaled to 25% in Ps CS4 (bicubic, muntoo's sample, scaled in one and two steps accordingly)?
Can anyone see the difference? But the difference is there:
#: gm compare -metric mse one-step.png two-step.png Image Difference (MeanSquaredError):
Normalized Absolute
============ ==========
Red: 0.0000033905 0.0
Green: 0.0000033467 0.0
Blue: 0.0000033888 0.0
Total: 0.0000033754 0.0
And can be seen if properly marked (gm compare -highlight-color purple -file diff.png one-step.png two-step.png):
1 and 2 makes my answer, which I hoped to keep brief, since other were quite elaborate ;).
That's it! :) Judge it yourself.