Multidrug-resistant HIV patients have limited ART options. Lenacapavir (LEN) is a capsid inhibitor that exhibits substantial antiviral activity in patients with therapeutic failure but is also proposed for PrEP. Herein, we assessed LEN susceptibility among ART-naive HIV patients with drug resistance in Mozambique. In this study, 63 patients with DRM against PIs, NRTIs, NNRTIs, and INSTIs were included. The gag (p24) and env fragments were amplified with a low-cost in-house protocol and sequenced with nanopore. HIVDR database from Stanford University was used to assess LEN resistance and geno2pheno to assess viral tropism and protease/maturation inhibitor-associated mutations. A total of 59 patients were successfully sequenced. About 29% had DRMs to PIs, 5% to NRTI, 83% to NNRTI, and 2% to INSTI. No DRMs to LEN were detected. Additionally, 42% of the sequences presented protease/maturation inhibitor-associated mutations. A relationship was observed between the E138A/G mutation and protease/maturation inhibitors (p = 0.004). We identified changes at the first codon position of position 56 of the p24 gag gene, which represents a key site for resistance to LEN. Also, codon 66 was highly conserved. Our results support the potential effectiveness of lenacapavir as a PrEP regimen or rescue therapy for patients with at least one drug-resistance mutation.