Super-resolution structured illumination microscopy (SR-SIM) provides an up to twofold enhanced spatial resolution of fluorescently labeled samples. The reconstruction of high-quality SR-SIM images critically depends on patterned illumination with high modulation contrast. Noisy raw image data (e.g., as a result of low excitation power or low exposure time), result in reconstruction artifacts. Here, we demonstrate deep-learning based SR-SIM image denoising that results in high-quality reconstructed images. A residual encoding–decoding convolutional neural network (RED-Net) was used to successfully denoise computationally reconstructed noisy SR-SIM images. We also demonstrate the end-to-end deep-learning based denoising and reconstruction of raw SIM images into high-resolution SR-SIM images. Both image reconstruction methods prove to be very robust against image reconstruction artifacts and generalize very well across various noise levels. The combination of computational image reconstruction and subsequent denoising via RED-Net shows very robust performance during inference after training even if the microscope settings change.