Evidence to define target ranges for tacrolimus (Tac) and mycophenolic acid (MPA) exposure after the first year of kidney transplantation is limited. We investigated the association of measurements at 1 year and repeated measurements of real‐world Tac‐trough levels (C₀) and abbreviated area under the curve from zero to 12 hours (AUC_0‐12h) of Tac and MPA with biopsy‐proven acute rejection (BPAR) between years 1 and 3 post‐transplant in 968 kidney transplant recipients (KTRs). Thirty‐five (3.6%) out of 968 KTRs experienced BPAR. Both Tac‐AUC_0‐12h (hazard ratio (HR): 0.39, 95% confidence interval (CI): 0.30–0.50, P < 0.001), Tac‐C₀ (HR: 0.46, 95% CI: 0.38–0.57, P < 0.001) and MPA‐AUC_0‐12h at 1 year (HR: 0.80, 95% CI: 0.68–0.94, P = 0.006), as well as repeated measurements of Tac‐C₀ (HR: 0.70, 95% credibility interval (CrI): 0.61–0.82, P < 0.001), and of MPA‐AUC_0‐12h (HR: 0.75, 95% CrI: 0.62–0.93, P < 0.001) were associated with BPAR. In our population, the recommended target range for Tac‐AUC_0‐12h at 1 year would be 75–95 ng*hour/mL and a Tac‐C₀ 5–7 ng/mL. The Tac‐AUC_0‐12h predicted BPAR better than Tac‐C₀ and identified KTRs with over‐ or underexposure despite supposedly adequate Tac‐C₀. We did not find evidence to recommend another target than the consensus range of 30–60 mg*hour/L for MPA‐AUC_0‐12h after the first year of transplantation. To our knowledge, this is a first study on the simultaneous exposure of Tac and MPA at year 1 and subsequent BPAR up to year 3, which may help define the therapeutic target window for the longer term.