Book from home. Don’t wait until you are over there to rent a vehicle. It is invariably cheaper to rent a car from the United States. Most major Ghanaian rental agencies are now online so you can just sit at the comfort of your home and then book a car online.
Always get the full rate. Rental companies love to stick it to you with low initial per-day rates, then add on all sorts of bells-and-whistles at the last moment (insurances, taxes, road fees, one-way charges to pick up in one city and drop of in another, etc.). If you’re visiting other countries on your trip and can arrange to pick up your rental elsewhere—buy any other insurances separately, from a third company. This will be cheaper and, from an insurance point of view, a bit safer. Also, don’t forget to inspect the car before you drive off. If any pre-existing nicks, scratches, dents, or other damage is not indicated and initialed by a local employee on your rental form before you leave, you will be liable for it when you return the vehicle (oh, and they will charge you an arm and a leg, believe me).
Don’t rent more than you need. We’re talking both the time you’ll need the car, and the kind of car you’ll need.
First, rent for as short a period as possible. Don’t rent a car for the full two weeks if you’re spending your first four days in Accra. You don’t need a car in Accra (driving is insane, street parking impossible to find, and garages expensive). In fact, you don’t need (or want) a car in any major city. Public transport in cities is fast, efficient, and cheap. Arrange to connect major cities by buses, and just rent the car for the shorter period when it is truly useful.
Second, don’t rent more than you need when it comes to the car itself. A smaller car will give you better fuel mileage, cutting down costs (and make it easier to navigate the winding road and narrow streets). If you can drive a manual, stick-shift is always cheaper than automatic (and also gives better fuel mileage).
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Forget driving in cities. See above. Not only are many cities—notably Accra and Kumasi—implementing a ZTL (“Zone of Limited Traffic”), which makes driving into the historic center either impossible or expensive, it just makes no sense to have a car in a city. Avoiding having a car in the city also niftily helps you avoid the airport pick-up surcharges, since the ideal itinerary has you picking up a car at a downtown office on your last day in one city (rather than at the airport when you arrive, only to drive the thing downtown and garage it for several days), and then dropping it off as soon as you arrive at the last big city. Congratulations. You just shaved several days (and several hundred dollars in rental and parking fees) off your rental period.
Look into short-term leases. If you’re renting a car for 17 days or longer, look into a short-term lease. All things being equal, this will usually cost less than a similar rental (especially as the period gets longer; at 30 days or more, only a fool would rent rather than leasing), plus it comes with all insurances, no deductible, and a brand new car.
Follow all driving rules and regulations and road signs. Ok, so everybody else speeds in Ghana. That doesn’t mean you should. You should drive defensively and cautiously. Yes, Ghanaian drivers are aggressive. Do not attempt to imitate them. See, they know the rules of the road—both the meanings of all the road signs and official regulations, and the unwritten rules of how people drive in Ghana (like how you should slow down and drive a bit on the shoulder to let a larger, faster car pass you, even if he insists on doing this on a blind curve of a meandering, two-lane country road). You do not know these rules, and that is a formula for trouble. Also: obey all no-parking signs. Ghanaian cops have gotten brutal about ticketing (and even towing) illegally parked cars (and any unpaid tickets will find their way to you via the car rental agency, which will attach a whopper of a fee for their troubles, along with the probable late penalties on the ticket itself).
Leave the driving to someone else. A rental car is great—but not always the right choice, even when you need to take a road trip in Ghana. The truth is, if you plan to take a classic daytrip or excursion, you can often hire a private driver and guide more cheaply than it would cost you in rental fees, fuel, tolls, and sight admissions to do it on your own. Plus, this way someone else—who already knows where he’s going—gets to worry about the logistics, traffic, parking, etc. You just have fun and see the sights. Also, this is the only truly fair way to tour, since otherwise the driver in your family or party would have to abstain.