What is the first or most ancient civilization to use a base-16, hexadecimal number system?
The only traditional use of hexadecimals that I know of, and that one is a bit of a stretch, is in Chinese weight units, e.g. one jīn (斤) was equal sixteen liǎng (兩), etc., see Non Base-10 Number Systems in Languages forum discussion. When suan pan (abacus) was introduced in China c. 200 AD it accomodated both decimals and hexadecimals, but presumably the use of weight units predates that by a lot. Apparently, Japanese adopted the abacus in 14th century, and the weight hexadecimals were still in use there and in China as late as in 1930s. Other than that, hexadecimals owe their relevance to the rise of the computers.
And yes, you read right about decimals on suan pan long before Indians invented the decimal notation. Chinese proto-decimal system was not fully positional, but that makes no difference for abacus calculations, see Has a digit ever been used to represent the number "10"?