The next-generation communication technologies are evolving towards increased flexibility in various aspects. Although orthogonal frequency division multiplexing (OFDM) remains as the waveform of the upcoming fifth-generation (5G) standard, the new radio provides flexibility in waveform parametrization (a.k.a. numerology) to address diverse requirements. However, managing the peaceful coexistence of mixed numerologies is challenging due to inter-numerology interference (INI). This paper proposes the utilization of adaptive guards in both time and frequency domains as a solution along with a multi-window operation in the physical (PHY) layer. The adaptive windowing operation needs a guard duration to reduce the unwanted emissions, and a guard band is required to handle the INI level on the adjacent band. The guards in both domains are jointly optimized with respect to the subcarrier spacing, use case (i.e., service requirement), and power offset between the numerologies. Also, the multi-window approach provides managing each side of the spectrum independently in case of an asymmetric interference scenario. Since the allowed interference level depends on the numerologies operating in the adjacent bands, the potential of adaptive guards is further increased and exploited with a medium access control (MAC) layer scheduling technique. The proposed INI-based scheduling algorithm decreases the need for guards by allocating the numerologies to the available bands, considering their subcarrier spacing, power level, and SIR requirements. Therefore, INI management is performed with a cross-layer (PHY and MAC) approach in this study. The results show that the precise design that accommodates such flexibility reduces the guards significantly and improves the spectral efficiency of mixed numerology systems.