At the end of a rainy day and evening that saw the schedule badly disrupted, Karlovic rallied past Blake in a first-round match 6-7 (2-7), 3-6, 6-4, 7-6 (7-2), 7-6 (7-2).
Blake had announced prior to the tournament this would be the last competitive appearance of his 15-year career.
The 33-year-old American rose as high as No. 4 in the world in 2006 and was ranked 100th this week. He won 10 tournaments, the last two coming in 2007.
Murray defeated Michael Llodra 6-2, 6-4, 6-3 to set up a second-round meeting with Leonardo Mayer. Del Potro moved on by downing Guillermo Garcia-Lopez 6-3, 6-7 (5-7), 6-4, 7-6 (9-7). He will next meet Lleyton Hewitt, who ousted Brian Baker 6-3, 4-6, 6-3, 6-4.
After rains delayed play during the afternoon, tournament officials postponed most of the women's matches in a bid to complete the first round of the men's draw.