The teams split a four-game series.
Matsuzaka (8-3) gave up a solo homer to Shin-Soo Choo in the first inning but limited the Indians to just four other hits until he was removed in the ninth. He struck out six in helping Boston win for the ninth time in 14 games.
Cleveland starter Josh Tomlin, making the third appearance of his major league career, retired the first 10 men he faced before giving up a single to Marco Scutaro in the fourth. After David Ortiz flew to left for the second out of the inning, Tomlin walked both Victor Martinez and J.D. Drew.
Beltre followed by hitting a 1-0 pitch out to left for the eighth grand slam of his career and his 20th homer this season.
Tomlin (1-1) did not allow another run in a seven-inning stint that resulted in his first big league loss.
Hideki Okajima relieved Matsuzaka and gave up a run on two hits before Jonathan Papelbon was called on to earn his 26th save.