The hosts scored six tries on Saturday to back up last week's 34-15 win over the South Americans in Tokyo.
Skipper Atsushi Sakate got Japan off to a flying start when he crossed after five minutes, and three penalties from five-eighth Takuya Yamasawa quickly gave the home side a 14-0 lead at Mikuni World Stadium.
They stalled for a time after that, but centre Dylan Riley crossed off turnover ball just before halftime, flanker Ben Gunter touched down soon after the break and South African-born winger Gerhard van den Heever scored a try to mark his Test debut.
A penalty try on the hour mark took the lead to 36-0 and Riley's centre partner Yusuke Kajimura scored the final try for the Cherry Blossoms after Uruguay flanker Santiago Civetta had been sent to the sin bin.
Lee Seung Sin came on for his debut in place of Yamasawa, who had missed four conversions, and slotted the extras after Kajimura's five pointer extended the lead to 43-0.
Los Teros finally got on the board through number eight Manuel Ardao six minutes from time with Japan a man down after prop Keita Inagaki had been shown a yellow card.
The 2019 World Cup quarter-finalists face 2023 tournament hosts France at Toyota Stadium next Saturday with the second Test at the National Stadium in Tokyo the following week.
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