Canada would investigate the case, because it is a murder on Canadian ground. Assuming the killer is identified, and is found to be in the USA (citizenship doesn't matter, just the location), Canada will send an extradition request to the USA. Assuming Canada provides enough evidence for a prosecution, and there's nothing unusual like the killer having diplomatic immunity, the USA will extradite them. Then Canada will take them to court and they will be found guilty or innocent, depending on the strength of the evidence.
For other crimes the situation could be different. The USA for example will prosecute quite a few crimes that happen outside the USA. For example US citizens bribing someone outside the USA. So if the situation was the same except it's not murder but a US citizen bribing someone in Canada, the USA might take the extradition request and say "Thank you very much for that evidence, but we'll prosecute him or her ouselves in the USA".
PS. "US citizen crosses border" is not needed. It's the same for anybody committing a crime in Canada and then travelling to the USA, Canadian citizen, US citizen, or say Chinese citizen, all the same.