Cognitive radio (CR) technology has the potential to detect and share the unutilized spectrum by enabling dynamic spectrum access. To detect the primary users’ (PUs) activity, energy detection (ED) is widely exploited due to its applicability when it comes to sensing a large range of PU signals, low computation complexity, and implementation costs. As orthogonal frequency-division multiplexing (OFDM) transmission has been proven to have a high resistance to interference, the ED of OFDM signals has become an important local spectrum-sensing (SS) concept in cognitive radio networks (CRNs). In combination with multiple-input multiple-output (MIMO) transmissions, MIMO-OFDM-based transmissions have started to become a widely accepted air interface, which ensures a significant improvement in spectral efficiency. Taking into account the future massive implementation of MIMO-OFDM systems in the fifth and sixth generation of mobile networks, this work introduces a mathematical formulation of expressions that enable the analysis of ED performance based on the square-law combining (SLC) method in MIMO-OFDM systems. The analysis of the ED performance was done through simulations performed using the developed algorithms that enable the performance analysis of the ED process based on the SLC in the MIMO-OFDM systems having a different number of transmit (Tx) and receive (Rx) communication branches. The impact of the distinct factors including the PU Tx power, the false alarm probability, the number of Tx and Rx MIMO branches, the number of samples in the ED process, and the different modulation techniques on the ED performance in environments with different levels of signal-to-noise ratios are presented. A comprehensive analysis of the obtained results indicated how the appropriate selection of the analyzed factors can be used to enhance the ED performance of MIMO-OFDM-based CRNs.