Uganda struggled to make contact off Castillo, who allowed four fair balls and four foul balls and struck out 14.
Seven straight LLWS champions started the tournament 2-0, as did 12 of the past 13 winners. Only Georgia in 2007 lost one of its first two games before going on to claim the title.
Castillo finished the shutout two pitches short of Little League's 85-pitch limit after his defense caught Joshua Olara in a rundown to end the game. Castillo went 2-for-3 at the plate and scored twice.
Joel Flores hit a first-inning grand slam to give Venezuela an early lead.
Felix Canpara had Uganda's lone hit, a single to center field in the fifth.
Venezuela will play Wednesday against the winner of Japan vs. Mexico. Uganda remains alive in this modified, double-elimination tournament, playing Monday vs. Taiwan.
Pennsylvania 9, South Carolina 8
Jaden Henline hit a two-run double in the sixth inning to give Lewisberry, Pennsylvania, a 9-8 victory over Taylors, South Carolina.
Lewisberry, two hours from Williamsport, won with the three-run inning after squandered a 6-0 fourth-inning lead. Henline hit the walk-off double after allowing four two-out runs in the top of the inning.
Lewisberry advanced to Wednesday's winner's bracket final against Pearland, Texas. Kaden Peifer led off the sixth with a home run that pulled Lewisberry within a run. Adam Cramer walked, Braden Kolmansberger doubled and Cole Wagner walked before Henline slammed a 2-0 pitch down the left-field line and brought most of the fans to their feet.
"We talk about this. Everyone has a dogpile at third on Jaden, and me and Cole are on the side doing a happy dance,'' Komansberger said. "Then I gave Jaden a high-five. I didn't want to be on the bottom of that because I didn't want to get hurt.''
Taylors, which plays an elimination game Monday against Bowling Green, Kentucky, scored four runs each in the fourth and sixth innings to take an 8-6 lead against a team that had won every game by seven runs or more this summer. Alex Edmondson hit a three-run, fourth-inning home run and Brock Myers hit a two-out, three-run triple in the sixth to put Taylors ahead for the first time.
Japan 3, Mexico 1
Pinch-hitter Fukutaro Kiyomiya homered in the bottom of the fifth inning, and Tokyo pitchers Nobuyuki Kawashima and Daiki Fukuyama shut down Mexicali Baja California, Mexico, in a 3-1 victory.
Kabu Kikuchi gave Japan a 2-0 lead in the first when he singled home Shingo Tomita and Yugo Aoki. Aoki finished 3-for-3, all singles.
Kawashima struck out five and walked none in four shutout innings for the win. Jose Reyes took the loss for the Mexican team, allowing three runs on six hits in 5 2/3 innings before leaving at 87 pitches.
Gerardo Lujano homered for Mexico in the sixth.
The Kitasuna Little League also represented Japan in winning the 2001 and 2012 LLWS titles, with return trips in 2007 and 2014. Mexico drops into the elimination bracket to face Uganda on Monday.
Texas 8, California 4
Ben Gottfried hit a two-run homer and threw 4 innings of three-hit ball as Pearland, Texas, beat Bonita, California, 8-4 to improve to 2-0.
Gottfried allowed no earned runs, struck out seven and stifled a team that had hit 90 home runs during 17 straight all-star wins. His sixth-inning home run made it 8-1.
Isaac Garcia closed out the win for a second straight Series game despite allowing a Dante Schmid three-run, sixth-inning homer.
Texas advanced to play Lewisberry, Pennsylvania on Wednesday, with that winner going to Saturday's U.S. title game.
Texas scored five third-inning runs, four with two outs. Pinch hitter Raffi Gross provided the big blow, driving the first pitch he saw well over the left-field fence for a two-run homer and a 4-0 lead. Garcia then added an RBI single, and another runner scored on an error.
Zack Mack had two RBIs for the Southwest champions, and his first-inning RBI single put Texas up to stay. Levi Mendez hit a third-inning RBI double for California, which dropped into the losers' bracket and will play Monday against Cranston, Rhode Island.
The Associated Press and ESPN Stats & Information contributed to this report.
Venezuela blanks Uganda in Little League World Series
Luis Castillo pitches a one-hit shutout and hits a two-run home run in Venezuela's 7-0 win over Uganda.