Ueno-san wa Bukiyou centers on Ueno, the brilliant but hopelessly awkward head of her middle school's science club. In the lab, she turns everyday problems into strange little demonstrations of genius, creating devices that can turn any liquid into drinkable water, neutralize the worst smells, or even generate dark matter for concealment. Yet none of that technical talent helps her with the one problem she cannot solve: she is completely in love with Tanaka, her calm and mostly indifferent fellow club member, and she is too flustered to confess while he remains oblivious to what she feels.
Determined to make Tanaka blush before she does, Ueno keeps coming back with one invention after another, testing improvised gadgets and awkward traps in increasingly risqué experiments. Each attempt is less a scientific breakthrough than another chance for embarrassment, as her plans collide with Tanaka's deadpan reactions and her own panic. With the help of Yamashita, her stone-faced classmate and devoted wingwoman, she throws herself into a string of lewd, awkward, and very human comedy episodes built around her hopeless crush.