Background: Long-term treatment with lithium can cause kidney damage. It has been hypothesised that single daily lithium dosing (SDD) minimizes kidney damage and SDD, given in the evening, has been widely endorsed by the medical community. However, kidney physiology suggests that SDD in the evening might maximise rather than minimise kidney damage. This review aims to assess if SDD compared with multiple daily lithium dosing (MDD) results in less kidney impairment. Methods: This PROSPERO-registered (CRD42024537460) systematic review was conducted in accordance with the PRISMA guidelines. PubMed and Web of Science were searched to identify studies investigating the effect of different lithium dosing regimens on kidney function, published up to 31 December 2024. Owing to substantial heterogeneity across studies, outcomes were synthesised narratively in accordance with the SWiM (Synthesis Without Meta-analysis) reporting guideline. Study validity was assessed across four domains: (a) kidney outcome adequacy, (b) statistical power, (c) control of confounders, and (d) methodological rigour. Certainty of evidence was evaluated using the GRADE approach. Findings: Of 709 records screened, 19 studies and one case report were included, comprising 6787 patients. The largest study, analysing 5751 patients, did not report the number of patients on SDD or MDD. The remaining studies, including the case report, included 492 patients on SDD and 576 on MDD. Only one study was of fair validity, finding no difference in kidney outcomes between dosing regimens. The remaining 18 studies and the case report were of poor validity. The certainty of evidence for SDD in terms of kidney protection was very low. Interpretation: Current evidence does not support the hypothesis that a lithium dose given as SDD in the evening, compared to MDD, is superior for the prevention or containment of kidney impairment.