I think the simplest case is to look at work due to gravity:
When, let's say you throw in a rock upwards, we know conceptually that the work done is negative since the weight is directed downwards and the displacement is upwards, also, the gravitational potential energy is given by U = mgh (m = mass, g = acceleration due to gravity, h=height (relative to some reference)). The equation W=U1-U2 is consistent with this, when we throw a rock upwards, U2>U1 and hence W<0 (negative), in the other case when we drop a rock, U2<U1 and hence W>0 (positive). Thus the equation is consistent with our idea of work.
I think, this would help if you want a more intuitive approach on this.