Aside from a short stopover in Frankfurt, I have never visited Germany so I have decided to make it my next trip in September due to a cheap flight I found. I will be flying into Berlin and then back home from Munich. How should one spend about 2 weeks on the ground there? I enjoy big cities, food and natural scenery.

Ideally, I don't want to change cities every 2 days either. Also, my time in Munich will coincide with the start of Oktoberfest. Is it enjoyable if you're traveling by yourself? I looked into it a bit and it might be awkward to be seated at a table full of strangers.

I could spend a week in Berlin, and I have several times. I love that city.

Hamburg is a 2 hour train ride and I found it a wonderful city. I spent a great weekend there. It was in the summer though.

Cologne was a fun weekend destination.

You could spend the entire 2 weeks in Bavaria if you wanted. Nuremburg, Regensburg, the castles, and Munich and the Alps.

You have lots of choices. German cities are easy to navigate, transit is usually excellent. Its easy to get to cities by train. Flights are cheap and often.

You pretty much cannot go wrong. I travel solo almost exclusively, and I have found Germans amongst the most affable people to meet and get to know as a single traveler. Its become one of my favorite countries to travel in.

I will focus only your question regarding Oktoberfest.

First of all you should start looking into hotels early since Oktoberfest is the busiest time in Munich with a lot of tourists. Prices start to go up real quickly. Second if you enjoy Oktoberfest or not depends on your personal taste. Do you like large festivals with a lot (I mean really a lot of people, of which a lot are at least tipsy), loud music and hearty meat heavy food? If yes you will have a great time. Is it enjoyable by your own? I would say yes since your will sit with strangers on a large table so that you do not stay alone. By the way you have a big chance to meet Americans, Australians, New Zealanders, etc. but probably not locals. If you don't like to meet people you do not know than Oktoberfest might not the right place for you or at least you will miss out a lot since you might not enjoy the atmosphere in the large tents.

Berlin and Hamburg are my favorite German cities, you could easily spend 8 days in both. Berlin is rich in museum (art, history mostly) and a very changing cityscape due to its history. There are lots of very different neighbourhood, restaurants and happenings. Hamburg has local foods, a different cityscape than everywhere else in Germany and lots of neighbourhoods. I was personally disappointed by Munich but think I should give it another chance. Cologne is very disappointing I think.
Bavaria has castles and nice villages that you could visit.

Travel within the country is easy. Trains are plentiful and the network extensive.

Totally depends what you prefer. If you like Roman history or churches Cologne is a must see. Regarding museums Berlin is (over all)!the winner and Munich and Hamburg are both unique. Personally I would avoid Munich during Octoberfest at all costs but that's a very special opinion of me.

Keep it simple

Berlin-Prague-Munich. 4 days in each plus train travel days. Do day trips from there is desired (e.g. Neuschwanstein castle from Munich)

Why also include Prague?

Whatever cities you visit, you will enjoy yourself I think. As others have stated, suggestions may be based on your interest.

In Munich, visit the Deutches Museum, watch surfers in the English Gardens and then stroll around (be advised, some of it is clothing optional),and while it will be a madhouse during Oktoberfest, eat and drink at the Augustinkeller.

We had luck with award nights at the Aloft near the Oktoberfest grounds. Good location.

As far as the rest, I second Berlin. Amazing city.
Also, make sure you visit a small town. Find the town center, find a bar or restaurant, have a drink and some food.

Amazing city half way between Berlin and Munich?
To cut down travel time, I would not go all the way to the Cologne. Other options would be Dresden and Nuremberg. But to cut down on the hotel hopping, the three mentioned above are good choices.

IIRC though, the trip from Prague to Munich is best by bus for time.

I know it�s a nice city and it�s relatively conveniant located. But if someone asks for German literary it�s not the logical choice.
Agree Cologne is not "on the way", same with Hamburg. But it�s also not that unconveniant. Compared with U.S. distances all near by.

Berlin is great. It is easy to spend a week there. Then train south - lots of possibilities: Potsdam, Dresden, Leipzig, Nuremberg, then Munich. Within an hour of Munich are Augsburg and the starnberg area. And dachau.

I love Munich but I'd minimize the time in Frankfurt; from FRA airport, you could go directly to Mainz and the stretch of Rhein with the castles. D�sseldorf is lovely. You might want to consider going to a wine village briefly; the town of Rudesheim is one of the easier and more convenient ones to visit but the Mosel valley is nice too, with good scenery.

Do a trip Berlin-Dresden-Leipzig-Nuremberg-Munich.

Berlin is just great for partying and all the historical sightseeing. Dresden is just a beautiful city with lots of things to do there, same goes for Leipzig and Nuremberg. You can travel between those cities by train, which is fast and easy. You will also see different regions of Germany that way, be able to taste different German-style food and beer.

My (totally biased) suggestion:
I would start with 3 days in Berlin to do some sightseeing. Enjoy the Museumsinsel (Pergamonmuseum, Nationalgalerie, Bode-Museum, etc.) and maybe the "Dokumentationszentrum Berliner Mauer", an exhibition about the Berlin wall. See the Reichstag, the Brandenburger Tor and all the other "must-see"-Spots.

Then I would suggest to go to Cologne by train (take the direct ICE, 4:20 hours) and stay in Cologne for 3-4 days. Cologne itself has the "K�lner Dom" (cathedral), a couple of art museums (Museum Ludwig, Wallraf-Richartz Museum). Do see the "R�misch-Germanisches Museum", an history museum about the romano-germanic history of Cologne. And much more.
Some ideas for trips from Cologne include Bonn (capital from 1949 - 1990) for the history of the recent period (i.e. the "Haus der Geschichte" - the House of the History or the Beethoven House) or a trip to Ruhrgebiet to learn about the mining history there and how it has changed the area (i.e. "Zeche Zollverein" in Essen or the "Deutsches Bergbau-Museum", the mining museum in Bochum).
In Cologne enjoy the local beer house culture with a "K�lsch", the only language you can drink as well. Or more. Or an "Alt" if you dare to order ... ;-)
If you need more information about Cologne, feel free to contact me.

After that take an direct IC train to Heidelberg (2:40 hours). Heidelberg is a nice town with a small but good preserved middle age old town. And as a bonus: The IC trains from Cologne to Stuttgart are going through the UNESCO world heritage middle rhine valley. Another option would be Mainz or Stuttgart. In Heidelberg, stroll though the city (Castle, Old Town, The Philosopher's Way) or go on a tour along the Neckar area. Stay here for 2 nights.

Then off to Munich (3 hours by IC train from Heidelberg, change trains in Stuttgart).
In Munich there is also a lot to see: Frauenkirche, "Englischer Garten", Nymphenburg Palace, Deutsches Museum, BMW museum, Olympic Park (from 1974).
Another idea might be to do some side trips, for example to Bamberg (beer, history) or N�rnberg / Nurmberg (history, beer). You may see my bias.
Or go to Garmisch-Patenkirchen to get on the top of Germany highest mountain with 2962 meter: The Zugspitze.

Personally I would stay in Bamberg or N�rnberg for at least one night, because I do like to taste local beers and would not want to go back after a nice evening with beer and food. But that's up to you. The trains from Munich to Bamberg take 1:45 (direct ICE, 2 hours with change of trains). Trains to N�rnberg take 1 hour (direct ICE) and trains to Garmisch-Patenkirchen take 1:30 (regional train).

A friendly piece of advice. DO NOT, while you are in the local beer house, proclaim that you do not like K�lsch bier.
Here is a picture of me being kindly escorted out by the locals after saying that.