Optimum experimental conditions for the photo-electro-Fenton (PEF) process using a lab-scale photo-reactor to treat a sanitary landfill leachate (SLL) were determined. The PEF process operational conditions were analyzed with a response surface methodology (RSM) that presented a high total carbon (TC) removal at the central point: current intensity of 2.3 A, H2O2 concentration of 9000 mg·L−1, Fe2+ concentration of 60 mg·L−1, an electrolysis time of 45 min and solution pH controlled at the range 3.5–4.5, reaching a minimum TC residual concentration of 344 mg·L−1 in the SLL, as well as 89 mg Pt-Co·L−1 of color, 254 nm = 0.18 a.u., 315 mg·L−1 5th day biochemical oxygen demand (BOD5), 782 mg·L−1 chemical oxygen demand (COD), improving the BOD5/COD = 0.4 ratio. The reaction byproducts were analyzed with gas chromatography-mass spectrometry (GC–MS). The generated byproducts were less toxic than the parent compounds found in the raw SLL. As the SLL toxicity was reduced, integration treatment strategies containing PEF processes and biological oxidation (BO) were studied. The best treatment strategy enabled the lethal concentration LC50% = 33% and reduced the residual TC concentration to 181 mg·L−1 through application of the PEF process. This possibly transformed recalcitrant compounds from raw SLL into more biodegradable substances (BOD5/COD = 0.53) facilitating the microbial activity in the posterior BO. This treatment strategy also produced a smaller number of identified byproducts, which confirms the good performance of the PEF process followed by BO.