This depends on what city or town you're talking about. Since you mention the US in your question, I'm going to answer from that point of view.
Manhattan, a part of New York City, famously has all three. According to NYCSubwayGuide, Uptown is the northern part (anything north of 59th Street), Downtown is the southern part (anything south of 14th Street), and Midtown is the part in between (between 59th Street and 14th Street). This is from the tradition in the northern hemisphere of referring to the cardinal direction north as "up" and south as "down". Additionally,
While Uptown, Midtown, and Downtown are geographic regions of Manhattan, the words uptown and downtown can also mean your direction of travel. If you head north or towards the Bronx or Queens, you can say you are headed "uptown"; if you head south or towards Brooklyn, you can say you are headed "downtown."
However, many towns only have a "downtown", which is basically the business district of the town and generally doesn't have anything to do with the cardinal directions (traditionally, such districts are centrally located). In fact, Cambridge Dictionary's American definition of downtown specifically references the "central part of a city". This is the most common meaning of downtown in the US.
On the other hand, the town where I live now only has an "Uptown". The town is built on a hill; our central business district is called "Uptown" instead of "downtown" because it runs along the ridge of the hill, so you must literally go up to get to Uptown from almost any other part of the town. Thus, when you say "I'm headed uptown" here you may be going either north or south, unlike in Manhattan. Another example of this is Charlotte, North Carolina, which also calls its "downtown" "Uptown" for similar historical reasons (and because they think it sounds cooler).
Unfortunately, this means that the only way to know for sure what is meant by one of these terms for a particular city or town is to look it up or ask a local. However, in most cases "downtown" will mean the city's main business district, wherever that happens to be.
5What dictionaries have you consulted? Is there any difficulty understanding the dictionary definition? – James K – 2017-07-21T20:11:20.997
2Beyond dictionary definitions, some examples (or situations for context) are needed. – user3169 – 2017-07-21T20:20:36.920
2@JamesK As the meanings of these terms varies greatly, even inside only a ten mile radius, a dictionary will necessarily leave out many nuances. For example, what downtown means in the Washington DC metro area varies greatly depending on location, context, speaker, and listener. Sometimes it means the waterfront area of Alexandria. Sometimes it means the corner of 236 and 123 in Fairfax, sometimes it means anywhere inside the border of D.C., and sometimes it means the area near the national mall in the northwest quadrant of D.C. This causes much confusion even among natives. – Todd Wilcox – 2017-07-23T05:44:02.347
1The OP has not stated that they have consulted a dictionary. They need to show that they have read the definition "Downtown = central part of city, dominated by businesses" and not understood it. As it stands, this question asks for the meaning of the words, and that can be answered by a dictionary. – James K – 2017-07-23T06:57:40.047
1@JamesK: As far as I have noticed, sometimes a dictionary definition doesn't match the real meaning used in the spoken language. Or it's just my feeling, I am not a native English speaker. That's why I have asked here. Moreover, according to what you have said, this could be applied to most of the questions here based on "difference between X and Y" and they should be closed? – Nikolas – 2017-07-23T09:17:04.093
1
Please edit to add the missing context. From the help centre "If you are asking about the meaning of a word or phrase, you should look up those words in a dictionary first. If you are still confused, be sure to summarize what you found when you did your initial research, and summarize that information in the question."
– James K – 2017-07-23T09:56:08.830