Background/Objectives: Anethole, a terpenoid with several pharmacologic effects, is the major constituent of the essential oil of Croton zehntneri (EOCz), Pax & K. Hoffm, Euphorbiaceae. Due to the mild renal toxicity associated with high doses of EOCz, its potential therapeutic effects on several diseases, and the fact that its chemical composition consists of 80% anethole, the renal effects of anethole in mice were investigated. Methods: Mice were randomly divided into eight groups, dosed daily as follows: Group 1—CTRL (control; vehicle only); Groups 2—A100, 3—A1252x, and 4—A250 (dosed with 100, 125 twice daily, and 250 mg/kg, per os anethole); Group 5—SUBAKI (i.p. albumin to induce hyperproteinemia and proteinuria; subclinical acute kidney injury); and Groups 6—SUBAKI+A100, 7—SUBAKI+A1252x, and 8—SUBAKI+A250 (per os anethole + i.p. albumin). Results: The A1252x and A250 groups significantly increased urinary proteinuria and interstitial inflammation (p < 0.001, for these groups). SUBAKI+A100, SUBAKI+A1252x, and SUBAKI+A250 showed a neither protective nor additive effect in the proteinuria induced by anethole and by administered albumin. The anethole-induced proteinuria was spontaneously reversible in approximately 4 weeks. In vitro experiments showed that anethole (300 µg/mL) inhibits albumin uptake from the culture medium by tubular cells. Conclusions: Anethole at high doses bears renal acute toxicity that, although mild and spontaneously fully reversible, must be taken into consideration in a cost–benefit analysis.