Purpose To optimize a selective inversion recovery (SIR) sequence for macromolecular content mapping in the human brain at 3.0T. Theory and Methods SIR is a quantitative method for measuring magnetization transfer (qMT) that uses a low‐power, on‐resonance inversion pulse. This results in a biexponential recovery of free water signal that can be sampled at various inversion/predelay times (tI/tD) to estimate a subset of qMT parameters, including the macromolecular‐to‐free pool‐size‐ratio (PSR), the R1 of free water (R1f), and the rate of MT exchange (kmf). The adoption of SIR has been limited by long acquisition times (≈4 min/slice). Here, we use Cramér‐Rao lower bound theory and data reduction strategies to select optimal tI/tD combinations to reduce imaging times. The schemes were experimentally validated in phantoms, and tested in healthy volunteers (N = 4) and a multiple sclerosis patient. Results Two optimal sampling schemes were determined: (i) a 5‐point scheme (kmf estimated) and (ii) a 4‐point scheme (kmf assumed). In phantoms, the 5/4‐point schemes yielded parameter estimates with similar SNRs as our previous 16‐point scheme, but with 4.1/6.1‐fold shorter scan times. Pair‐wise comparisons between schemes did not detect significant differences for any scheme/parameter. In humans, parameter values were consistent with published values, and similar levels of precision were obtained from all schemes. Furthermore, fixing kmf reduced the sensitivity of PSR to partial‐volume averaging, yielding more consistent estimates throughout the brain. Conclusions qMT parameters can be robustly estimated in ≤1 min/slice (without independent measures of ΔB0, B1+, and T1) when optimized tI‐tD combinations are selected.