The very first episode sets up a potential romance between the two with Dwayne catching a crush on Denise. If Lisa Bonet had not gone back to The Cosby Show and stayed on ADW would she and Dwayne had been endgame?

While the first episode of A Different World established Dwayne Wayne’s crush on Denise Huxtable, there is strong evidence that they were not intended to be "endgame" even if Lisa Bonet had stayed.
Instead, Denise’s departure allowed the show to pivot toward its ultimate core couple: Dwayne and Whitley Gilbert.

1. Denise as a "Vehicle" Rather than a Romantic Lead
Originally, the show was strictly a vehicle for Denise Huxtable to explore life at an HBCU. In the early development stages, the primary dynamic was intended to be between Denise and a white roommate (originally planned for Meg Ryan, eventually played by Marisa Tomei) to showcase racial dynamics. Dwayne was initially a side character defined by his persistent, often comical, pursuit of Denise rather than a serious romantic partner for her.

2. The Lack of Mutual Chemistry
Unlike the later relationship with Whitley, which featured a complex "frenemies-to-lovers" arc, the Denise/Dwayne dynamic was largely one-sided.

Denise's character arc: Denise was written as a "free spirit" and "wild child". Her eventual storyline on The Cosby Show—where she unexpectedly married Martin Kendall, a man she met in Africa—aligned with her flighty, non-traditional nature.

Dwayne's evolution: Producers noted that viewers didn't truly gravitate toward the Dwayne/Denise pairing. It wasn't until Debbie Allen took over in Season 2 and noticed the natural chemistry between Kadeem Hardison and Jasmine Guy that the show shifted its romantic focus.

3. The "Debbie Allen Revamp"
When Lisa Bonet left due to her real-life pregnancy in 1988, Debbie Allen was brought in to fix a show that many felt lacked authenticity.

Allen decided to lean into the ensemble cast, specifically elevating Whitley and Dwayne.
Even if Denise had remained, she likely would have continued as an experimental, bohemian lead rather than settling into a domestic "endgame" with Dwayne, whose maturity only truly developed through his challenges with Whitley.