Smits will lead the cast of the legal drama Bluff City Law, while Russell Hornsby and Arielle Kebbel will play investigators in Lincoln, an adaptation of the serial-killer novel, The Bone Collector.
Penn is to star in Sunnyside, a comedy about a disgraced New York City councilman seeking redemption by helping immigrants become U.S. citizens.
Drescher and Adam Pally have signed on to play a mother and son in Indebted, a sitcom about what happens when a financially strapped, middle-aged couple move in with their adult child and his wife.
In The Kenan Show, Kenan Thompson plays the enthusiastic father of two young girls who finds himself undermined by his father-in-law.
Whitford will play a Princeton University music professor who takes over a small-town church choir in the comedy, Perfect Harmony.
NBC also renewed its current hits This is Us, Manifest, New Amsterdam, Law & Order: SVU, Good Girls, Superstore, Blindspot, The Good Place, The Black List, Brooklyn Nine-Nine, Will & Grace and its Chicago franchise.
"We came into this season from the vantage point of extreme stability, but without any complacency," George Cheeks and Paul Telegdy, co-chairmen of NBC Entertainment, said in a press release on Sunday.
They added: "Comedy is at the heart of the NBC brand, and we've picked up four new comedies that we think viewers will love for generations to come. Our new dramas will compel audiences to tune in week after week to our network while also delivering binge-worthy story-lines, and our unparalleled alternative programs continue to delight audiences of all ages, providing enviable launch pads for many of our new shows."