The American became the fifth first-time winner on the ATP tour this year and the first US Clay Court wild-card champion since Mardy Fish in 2006.
Sweeting fell to the court in jubilation and fatigue after the hard-fought second set and later took a cannon ball victory dive into the River Oaks Country Club pool.
Sweeting earned $80,650, and Nishikori took home $42,450.
Nishikori was trying to win the tournament to give inspiration to his tsunami-torn country and he almost pulled off a comeback late in the second set.
Sweeting, trailing 5-4 in the second set, served in the 10th game and had to overcome three set points before holding on a lob error by Nishikori that fell behind the line. The game lasted for 26 points.
The tiebreaker got tight when Sweeting double-faulted to bring the score to a 3-3 tie. Two errors by Nishikori and a forehand volley winner by Sweeting brought it to match point and it ended when Nishikori's forehand skipped wide.
Sweeting entered the tournament ranked No. 93. The victory will kick his ranking up to about 71.
Nishikori entered ranked 61st. A victory would have boosted his rank to about 41st. His second-place finish will raise his ranking to about 49th.
Shuzo Matsuoka is the highest-ranked Japanese player ever at No. 46 in 1992.
One year ago, Nishikori was unranked while recovering from elbow surgery in 2009.
