Australian Open champion Djokovic faced just two service breaks, while converting eight of 13 against his opponent.
Djokovic, a 2011 winner at Flushing Meadows who fell to Andy Murray in five sets in last year's final, next faces 43rd-ranked Marcel Granollers of Spain after he beat 109th-ranked American wild card Tim Smyczek.
Berdych will play Swiss Stanislas Wawrinka in the round of 16 after the ninth seed squeezed past Cypriot Marcos Baghdatis 6-3 6-2 6-7(1) 7-6(7).
The big-serving Berdych upset 17-time major champion Roger Federer in the quarter-finals at Flushing Meadows last year before losing to Murray in four sets in the semi-finals.
Larsson got off to a good start in her home tournament, breaking in the opening game, and was 3-1 in front early but the eight seeded Swede only went on to win two more games as Serena took control.
It was the 53rd WTA title of Williams' career and puts her level with Monica Seles for ninth on the all-time list in the Open era.
Meanwhile in Bad Gastein, Austria, Yvonne Meusburger delighted the home fans by winning the first title of her career against Andrea Hlavackova of Czech Republic 7-5 6-2 .
Meusburger is ranked only 86th in the world but enjoyed a fantastic tournament – not dropping a single set all week.
