We investigate the optimal signal detection problem in large-scale multiple-input multiple-output (MIMO) system with the generalized spatial modulation (GSM) scheme, which can be formulated as a closest lattice point search (CLPS). To identify invalid signals, an efficient pruning strategy is needed while searching on the GSM decision tree. However, the existing algorithms have exponential complexity, whereas they are infeasible in large-scale GSM-MIMO systems. In order to tackle this problem, we propose a memory-efficient pruning strategy by leveraging the combinatorial nature of the GSM signal structure. Thus, the required memory size is squared to the number of transmit antennas. We further propose an efficient memory-bounded maximum likelihood (ML) search (EM-MLS) algorithm by jointly employing the proposed pruning strategy and the memory-bounded best-first algorithm. Theoretical and simulation results show that our proposed algorithm can achieve the optimal bit error rate (BER) performance, while its memory size can be bounded. Moreover, the expected time complexity decreases exponentially with increasing the signal-to-noise ratio (SNR) as well as the system’s excess degree of freedom, and it often converges to squared time under practical scenarios.