6.5 Hour layover in Paris - Can I do anything?

No -- it is madness to attempt a trip into Paris with anything less than 7 hours and even that is pushing it. It is an hour about to get through immigration and another hour into town and an hour back to the airport -- so 3 hours comes right off the top even assuming you really have 6.5 hours on the ground and the plane is on time. You should be at the airport 3 hours before a long haul international flight.

The stakes are very high in missing the ongoing plane; not worth the risk.

You mean your arrival time is 16:45 (4.45pm) ?
No, I wouldn't do it. You are looking at ...
1 hour to get off the plane and thru the airport.
1 hour into central Paris by RER.
1 hour for return to airport by RER.
2-3 hours for airport reprocessing.
That's a total of 5-6 hours, just not worth risking it, especially during Friday's busy peak.

Or do you mean that you are landing at 4:45 in the early morning, with a flight to South Africa at 11:15 am? Or have you accounted for the landing and departure formalities and you actually have a clear six and a half hours free, such as landing at 04:45 and flying out at 3pm?

Checking Delta flight from San Francisco, looks like a 4:45 PM (16:45) arrival at CDG and an 11:25 PM (23:25) departure to Johannesburg.
So assuming luggage is checked through to Johannesburg and you have a continuing boarding pass.
It will take about 45 min to an hour to get off the plane and get through immigration, walk to the train station. The train into Paris (suggest station St Michel/Notre Dame) takes about 45 minutes. You will want to be back at the airport 9:30 PM, so I figure you have 2 about hours in central Paris. Enough time look at the Eiffel Tower from afar, walk by the Seine, look at Notre Dame, then head back. You decide if it is worth it. The train costs 10 EUR each way.

Thanks everyone, yes I arrive at 4:45pm. I will have checked luggage and a small backpack and a purse as my carry on. I am willing to take a taxi or other means if it is quicker. Something to this about for sure.

Are we talking November, when it will be dark, or in Spring daylight next May ??

Train will definitely be quicker, as well as a whole lot cheaper. Train takes you to the center of Paris with no traffic to worry about and they go about every 7 minutes. Get a Zone 1-5 Mobils (day pass) for 17.30 EUR which will cover round trip from/to the airport as well as any quick Metro or bus rides while in Paris.

The Mobilis Day pass is not valid for travel to and from the airports.

Yep, 10 EUR each way.

I will be going the end of the month so I'm guessing it will still be fairly light out.

I wouldn't risk it. I tried something like that once on a slightly longer layover in London. It was a waste of time - we saw nothing because we were worried about making it back in time. And, more importantly, it was our first view of London, like it will be your first view of Paris, and so we didn't have any real practical knowledge of how to get around and what we can do quickly etc. Our trip consisted of taking public transit in, feeling overwhelmed and taking public transit back.

Don't some of the hotels in the airport have short term rental for just a few hours? Or a day pass to one of the lounges? Going from one long flight to another it would be nice to take a shower and maybe a nap in a flat bed.

Sunset at the end of August is a couple of minutes before half past eight, PM.

The usual recommendation that I have seen is that you need 7 hours between flights to consider going into Paris from CDG. That being said, I think that you could do it but it will require real planning and a willingness to skip it or turn around if things are not going well. You can't waste time wandering around CDG trying to find the RER station so before you go, you would need to examine a map of CDG and look at http://parisbytrain.com/charles-de-gaulle-airport-cdg-to-paris-by-train/ and feel comfortable with what you will need to do and where you will need to go. Taking a taxi will be absolutely the wrong decision because of surface traffic. Then you should have either some euros or a card that you know will work at the ticket machines because if you have to wait in line to buy an RER ticket, that will probably eat up too much of your time. I'd allocate three hours for travel to and from Paris and clearing passport control. I'd plan to arrive 2.5 hours before my flights departure time. That give you 30 minutes in Paris. Pick the one thing that you want to see. I'd say Notre Dame because it is a simple trip -- RER B to St-Michel-Notre-Dame. The exit you want is at the back of the train at St-Michel-Notre-Dame; that's the one that comes out on Ile de la Cité in front of Notre Dame. Look around, walk over to the Seine and look at it and then get back on the train and head to CDG. Would I do it? No, but that is because I intensely dislike rushing around and worrying about making my flight and that stress would remove any joy from this trip for me. My husband and sister though would be all in for doing it so it really is a matter of how balance the risk versus the reward

Why don't you contact your airline and see if they will adjust your flight to at least give you an overnight in Paris? I did this recently in Amsterdam when I was on my way to Africa. I enjoyed a break from the long flights, a chance to start getting used to the time change, and a fun day of doing simple exploration in Amsterdam. There is no law that you must keep a grueling pace of long haul flight after long haul flight without a break.

Unless you can change the flight resign yourself to time in the airport (CDG I assume?). Do whatever you can to get a pass to your airline lounge, even if it is a splurge. You'll appreciate the space, food, libations.

For me I would at least want time for ...
RER from CDG to St Michel for Notre Dame.
RER from St Michel to Champ de Mars for Eiffel Tower.
RER return to CDG, via change at St Michel.

I would agree with most of the replies that going into Paris is just not worth the risk of missing your connecting flight. The time frames given are correct. That means that there will be no margin for error. If there is a delay in the RER train to CDG, problem with getting from the metro stop to the RER train, delay in getting past security, or you get lost and can not find the metro station or the correct RER platform, or you catch the non-direct train to CDG (delay of 15-20 minutes extra), you may miss your flight and the airline may make you pay extra since it was your fault, not theirs. Also, will you be able to enjoy seeing anything in Paris if there is this constant worry about getting back to CDG in time. Lastly, if you have never been to Paris, I guarantee that you will get lost going to wherever you plan to go, or finding the Metro station, finding the correct metro stop, etc. I have been to Paris and used the RER and metro numerous times and know exactly which station and where to stop. Even I would not risk it. Forget about taxi back to CDG on a Friday night, the RER is the only way to go, if you want to risk it.

The stress induced by worrying about a missed flight would be a killer for me too. You know how stressed you feel when you have to get back to your car fearing that the parking meter has expired ? Multiply it !!

If the OP is going to Paris before August 27th (the post says end of the month but not the exact date), the RER C is not running from Saint-Michel-Notre-Dame to the Eiffel Tower.

Well, you all convinced me to not try it. I can't really change or extend my flight as i am there for a wedding and have plans with the prep as soon as I arrive. My travel partner used to live in Paris for 2 years and said it was my decision. I will look into the day pass for the lounge. The hotel option sounds good too. Thanks again.