The function of long non-coding RNA LHFPL3 antisense RNA 1 (LHFPL3-AS1) in cancer progression has been studied, while its role in nasopharyngeal carcinoma (NPC) remains unclear. This study aims to unravel the effects of LHFPL3-AS1 on NPC progression via microRNA (miR)-143-5p/homeobox A6 (HOXA6) axis. NPC tissues were collected and NPC cells were cultured. NPC cells were subjected to radiation therapy to construct the radiation therapy resistance NPC cell line. The levels of LHFPL3-AS1, miR-143-5p and HOXA6 in NPC cells and tissues were examined. LHFPL3-AS1, miR-143-5p or HOXA6 expression was changed and then transfected into radiation-resistant NPC cells to detect cell proliferation, colony formation, migration, invasion and cell apoptosis in vitro. The tumorigenesis in nude mice in vivo was conducted to detect tumor growth. The targeting relations among LHFPL3-AS1, miR-143-5p and HOXA6 were validated. It was discovered that LHFPL3-AS1 and HOXA6 expression was elevated while the miR-143-5p level was depleted in radiation-resistant NPC cells and NPC tissues. The silenced LHFPL3-AS1 or augmented miR-143-5p repressed the proliferation, colony formation, migration and invasion of radiation-resistant NPC cells, while accelerated cell apoptosis in vitro. Silenced LHFPL3-AS1 hindered tumor growth in vivo. MiR-143-5p deletion reversed the effects of reduced LHFPL3-AS1; while HOXA6 upregulation reversed the effects of enriched miR-143-5p. LHFPL3-AS1 sponged miR-143-5p that targeted HOXA6. It is concluded that the down-regulated LHFPL3-AS1 retards the development of radiation-resistant NPC cells via sponging miR-143-5p to modulate HOXA6. This study reveals novel therapeutic targets for NPC treatment.