As a kind of cast aluminum alloy with high strength, Al–Li–Cu–Mg series alloys exhibit desirable stiffness and formability, while a limited investigation has discussed the influence of cooling rate on microstructure and mechanical properties of these alloys. In this work, the effect of cooling rate during casting on microstructure evolution and mechanical properties of cast Al–2Li–2Cu-0.5Mg-0.15Sc-0.1Zr-0.1Ti alloy was investigated using a step-like iron mold. The results showed that the increased cooling rate refined the grain size and augmented the volume fraction of second phase in the as-cast microstructure. In the aging process, the rapid cooling rate markedly promotes precipitation and suppresses coarsening of the δˊ(Al3Li), T1(Al2CuLi) and Sˊ(Al2CuMg) phases, which plays a vital role in enhancing strength of the peak-aged alloy. In addition to diffusion and vacancy mechanisms, a Li-rich zone offers a new precipitation pathway for T1 precipitates. Notably, the rapid cooling rate of 16.1 °C/s significantly facilitated the formation and inhomogeneous distribution of the cubic σ(Al6Cu5Mg2) phase, which competed with the T1 and Sˊ phases for Cu and Mg atoms. Finally, the formation mechanism of the σ phase under different cooling rates was discussed, and the strengthening and fracture mechanisms were quantified. The present work is expected to enlighten the understanding of the microstructure evolution of Al–Li alloys with varied cast cooling rates.