World number six Blake, bidding for his 10th career title this week, brushed past fellow American Robert Kendrick 6-3, 6-2 in less than an hour in an evening encounter.
Blake, who won in Sydney earlier this month before losing to eventual finalist Fernando Gonzalez of Chile in the fourth round of the Australian Open, is making his third appearance at Delray Beach.
Kohlschreiber was broken five times by Italy's Davide Sanguinetti before losing 7-5, 6-3, his second successive defeat in the round-robin format.
The German was beaten by big-serving American Amer Delic in three sets the previous day.
The 24-year-old Delic will meet Sanguinetti to decide one of the quarter-final spots under the ATP's new round-robin tournament format.
Third-seeded Belgian Xavier Malisse, who won his second ATP Tour title at the Chennai Open earlier this month, edged past Colombia's Alejandro Falla 6-4, 7-6 in his opening match.
Malisse, the 2005 champion who lost to Germany's Tommy Haas in last year's final, broke his opponent twice before sealing his 21st victory in 27 appearances at Delray Beach.
"I enjoy playing here, and it's close to home," the Sarasota-based Belgian told reporters.
"The courts today were nice and slow for my game."
Other winners on Tuesday included Romania's Andrei Pavel and Teimuraz Gabashvili of Russia.
