Caltrans spokesman Steven Williams said "it will be a challenge for the next month" in the busy corridor, which feeds drivers going to and from the San Mateo-Hayward Bridge and other destinations.
At a briefing with reporters, Caltrans senior transportation engineer Scott McCrank said work on the $148 million project, which began in October 2007, is about two-thirds done and is expected to be completed by September 2011.
McCrank said the work will replace the existing cloverleaf interchange, which he said creates bottlenecks because cars have to weave and merge, with a "direct connector" which is aimed at making traffic flow more smoothly.
As part of the project, new traffic bridges are being built over I-880, which runs north and south, he said.
Beginning at 7 p.m. on Friday and continuing until 5 a.m. on Monday, the southbound I-880 to eastbound Route 92 connector ramp will be closed.
McCrank said motorists will exit southbound I-880 at the Tennyson Road off-ramp and then re-enter the freeway on the northbound Tennyson Road loop.
He said motorists familiar with the area may choose alternate routes, such as A Street or Winton Avenue to avoid the closure.
Trucks should use the official detour to Tennyson Road due to traffic and weight restrictions, according to McCrank.
He said the biggest closures will be on the weekend starting Friday, April 16.
Westbound Route 92 from downtown Hayward will be closed for 12 hours, from 8 p.m. April 16 to 8 a.m. April 17, McCrank said.
He said two connector ramps will be closed for 57 hours that weekend.
The closures mean that there won't be any access to the interchange for motorists traveling from north to west or west to south, McCrank said.
Traffic "might be busy" the night of April 17 when westbound Route 92 is closed, he said.
Caltrans already has electronic signs warning motorists about the construction work, according to McCrank.
He said many local drivers already are taking alternate routes, such as A Street or Winton Avenue, to avoid the interchange during busy phases of the work.
But Caltrans wants to make other drivers aware of the work as well, McCrank said.
The agency is trying to do most of the ramp closures on weekends to try to minimize delays for drivers during weekdays, he said.
