It's a saying. Say it right.
Times when it is appropriate to say, "Holy mackerel!":
1. When confronted with a fish possessing religious significance. For example, a fish being worshiped by a certain group of people or else a fish that possesses certain powers that seem divinely endowed, perhaps a fish that could fly or shoot lasers from its eyes or write catchy and inspiring pop songs.
2. When confronted by something very surprising, which might very well be a Holy Mackerel such as described above.
3. Whenever the heck you feel like! It's a free country, after all.