With Boston trailing 1-0 in the bottom of the first, Ortiz powered a homer to right off Ian Kennedy (3-4), scoring Dustin Pedroia ahead of him and putting Boston ahead for good in the first contest of a three-game inter-league series with the Diamondbacks.
Pedroia and Kevin Youkilis each had a pair of hits and an RBI for the Bosox, who won for the 20th time in their last 29 games at Fenway Park.
Clay Buchholz (9-4) got the win, striking out eight batters in 5 2/3 innings while surrendering three runs on seven hits but issuing only one walk.
Jonathan Papelbon notched his 14th save with a scoreless ninth.
Kennedy was lit up for six runs on nine hits over six innings. Justin Upton knocked a two-run double for the Diamondbacks.