Watch in the clip as Drew grabs Oprah's hand on "The Drew Barrymore Show" ... and doesn't let go for dear life ... propping it awkwardly under her chin as they chat.

She also later uses her arm to caress her arm slowly ... her actions leaving fans mortified, with one commenting online: "Drew, everyone doesn't want their hands held boo."

Another highlighted Oprah's discomfort, writing: "Oprah's body language was so clear she wanted her hand back" -- another adds: "Oprah's body language says it all. Drew is holding on too much. Oprah is trying to release her hand from Drew's grip. Drew is just too creepy and needy."

The handsy display came as Drew responded to Oprah praising her for starting her show without a live studio audience during the pandemic.

However, Oprah said she felt crowd interaction was necessary ... as Drew noted she'd observed Oprah spending time with her audience outside of her talk show -- thus leading to her success.