Forty-two refugees, belonging to five families, were greeted on arrival by the Uruguayan President, Jose Mujica.
They will spend two months in accommodation near the capital Montevideo where they will learn Spanish and  attend classes on local customs.
Other Latin American countries have taken Syrians in but Uruguay is the first to assume all resettlement costs.
Officials say the two-year resettlement programme will cost Uruguay around $3m (Â£1.9m).
They say the adults have already been guaranteed  jobs and the children have places in local school. A second group is due to arrive next year.
A small number of Syrian refugees have arrived in Uruguay from Lebanon.