Different drugs impact on different parts of the nervous system, so mixing uppers and downers is a way of mitigating side effects you don't want. For example a speedball, when someone injects heroin mixed with speed, to get the high of heroin without the drowsiness, etc. (Of course that's a drastic example, and make a tiny mistake and you're pretty much dead.)
It's not a black and white thing, different drugs all have different pathways and act on the nervous system in different ways.
E.g. mixing alcohol and amphetamines, you can drink much more without feeling drunk, yet you do become more social etc, it's supposedly quite bizarre. The problem with doing that is that as the amphetamines wear off, you can end up with alcohol poisoning due to the depressive effect of the alcohol alone, etc...
The same goes for people who take a ton of amphetamines and then take anti depressants when they begin to crash.
It's all about maximising the good effects of the upper / downer and minimising the bad ones. Weed for ex. could potentially take the edge off of an amphetamine high by chilling you out a bit, getting rid of the shakes, anxiety, etc..
